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Human culture, biology, and health were shaped dramatically by the onset of agriculture ~12,000 years before present (BP). Subsistence shifts from hunting and gathering to agriculture are hypothesized to have resulted in increased individual fitness and population growth as evidenced by archaeological and population genomic data alongside a simultaneous decline in physiological health as inferred from paleopathological analyses and stature reconstructions of skeletal remains. A key component of the health decline inference is that relatively shorter statures observed for early farmers may (at least partly) reflect higher childhood disease burdens and poorer nutrition. However, while such stresses can indeed result in growth stunting, height is also highly heritable, and substantial inter-individual variation in the height genetic component within a population is typical. Moreover, extensive migration and gene flow were characteristics of multiple agricultural transitions worldwide. Here, we consider both osteological and ancient DNA data from the same prehistoric individuals to comprehensively study the trajectory of human stature variation as a proxy for health across a transition to agriculture. Specifically, we compared ‘predicted’ genetic contributions to height from paleogenomic data and ‘achieved’ adult osteological height estimated from long bone measurements on a per-individual basis for n=160 ancient Europeans from sites spanning the Upper Paleolithic to the Iron Age (~38,000-2,400 BP). We found that individuals from the Neolithic were shorter than expected (given their individual polygenic height scores) by an average of −4.47 cm relative to individuals from the Upper Paleolithic and Mesolithic (P=0.016). The average osteological vs. expected stature then increased relative to the Neolithic over the Copper (+2.67 cm, P=0.052), Bronze (+3.33 cm, P=0.032), and Iron Ages (+3.95 cm, P=0.094). These results were partly attenuated when we accounted for genome-wide genetic ancestry variation in our sample (which we note is partly duplicative with the individual polygenic score information). For example, in this secondary analysis Neolithic individuals were −3.48 cm shorter than expected on average relative to individuals from the Upper Paleolithic and Mesolithic (P=0.056). We also incorporated observations of paleopathological indicators of non-specific stress that can persist from childhood to adulthood in skeletal remains (linear enamel hypoplasia, cribra orbitalia, and porotic hyperostosis) into our model. Overall, our work highlights the potential of integrating disparate datasets to explore proxies of health in prehistory.

Monitoring measurable residual disease (MRD) in acute myeloid leukemia (AML) plays an important role in predicting relapse and outcome. The applicability of the leukemia-initiating nucleophosmin1 (NPM1) gene mutations in MRD detection is well-established, while that of isocitrate dehydrogenase1/2 (IDH1/2) mutations are matter of debate. The aim of this study was to investigate the stability of NPM1 and IDH1/2 mutations at diagnosis and relapse retrospectively in 916 adult AML patients. The prognostic value of MRD was evaluated by droplet digital PCR on the DNA level in a selected subgroup of patients in remission. NPM1 re-emerged at relapse in 91% (72/79), while IDH1/2 in 87% (20/23) of mutation-positive cases at diagnosis. NPM1 mutation did not develop at relapse, on the contrary novel IDH1/2 mutations occurred in 3% (3/93) of previously mutation-negative cases. NPM1 MRD-positivity after induction (n = 116) proved to be an independent, adverse risk factor (MRDpos 24-month OS: 39.3±6.2% versus MRDneg: 58.5±7.5%, p = 0.029; HR: 2.16; 95%CI: 1.25–3.74, p = 0.006). In the favorable subgroup of mutated NPM1 without fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) or with low allelic ratio, NPM1 MRD provides a valuable prognostic biomarker (NPM1 MRDpos versus MRDneg 24-month OS: 42.9±6.7% versus 66.7±8.6%; p = 0.01). IDH1/2 MRD-positivity after induction (n = 62) was also associated with poor survival (MRDpos 24-month OS: 41.3±9.2% versus MRDneg: 62.5±9.0%, p = 0.003; HR 2.81 95%CI 1.09–7.23, p = 0.032). While NPM1 variant allele frequency decreased below 2.5% in remission in all patients, IDH1/2 mutations (typically IDH2 R140Q) persisted in 24% of cases. Our results support that NPM1 MRD even at DNA level is a reliable prognostic factor, while IDH1/2 mutations may represent pre-leukemic, founder or subclonal drivers.

Two achalasia patients with former complaints of heartburn were examined. Antisecretory drugs were used by the patients when dysphagia occurred. Barium X-ray and esophageal manometry were performed and achalasia was diagnosed in both patients. Twenty-four-hour pH-metry showed significant and long-lasting acid reflux during supine position. Prolonged reflux episodes can be explained not only by the swallow-unrelated transient relaxation of lower esophageal sphincter (LES) and mechanical damage of the esophageal body, but also by its chemical insensitivity. Thus preoperative detection of reflux should determinate either the operational procedure and the postoperative follow up of the patient.

The physiologic importance of afferent sensory pathways in the esophageal motor functions has been recently recognised. Capsaicin-sensitive sensory afferents were shown to play a role in the maintenance of mucosal integrity of the GI tract, and regulation of human esophageal motility. The aim of this study was to investigate the effect of topical application of capsaicin-containing red pepper sauce (Tabasco, 25%v/v, pH:7.0) suspension on the phasic activity of the human esophagus of healthy volunteers and patients with Barrett’s esophagus. Methods : The diagnosis of Barrett’s esophagus was based on the findings of esophagoscopy and histology taken from the squamocolumnar junction of the esophagus. Esophageal motility was measured by perfusion manometry before and after application of red pepper sauce. Results : Capsaicin containing red pepper sauce increases the motility response (LES tone, contraction amplitude, propagation velocity) of the human esophagus in healthy volunteers. This response failed in patients with Barrett’s esophagus. Conclusion : Impaired esophageal sensorymotor function may serve as one etiologic role in the development of Barrett’s esophagus.

Visceral hyperalgesia has been suggested to play a role in the development of symptoms presented by irritable bowel syndrome patients. Otilonium bromide was developed to block smooth muscle Ca release to control cramping pain of these patients. Aims: to determine whether otilonium bromide can influence sensory thresholds of patients suffering from irritable bowel syndrome. Methods: 15 patients with Rome-II positive IBS were tested by Synectics Visceral Stimulator Barostat using rapid phasic distension (870 ml/min). The sensory threshold for first sensation, stool, pain and maximum tolerable volume and pressure were measured. All of the parameters were tested before and 1 week after the initiation of otilonium bromide (Spasmomen, Berlin Chemie, 3×40 mg) therapy. Results: The perceptual thresholds for first sensation, stool, pain and maximum tolerable distention were, 8.8±1.7 Hgmm, 19.2±2.1 Hgmm, 26.3±2.8 Hgmm, 28.7±2.8 Hgmm for pressure, 90±21 ml, 145±28 ml, 208±25 ml, 213±28 ml for volume, before treatment, respectively. Otilonium bromide treatment did not influence the thresholds for first sensation and stool, 7.4±1.4 Hgmm, 20.7±4.6 Hgmm and 83±21 ml, 178±35.8 ml, respectively. The pressure threshold of pain was significantly higher 1 week after treatment (26.3±2.8 Hgmm vs. 29.1±5.5 Hgmm, P

INTRODUCTION: Biosimilar versions of filgrastim [recombinant human granulocyte colony-stimulating factor (rhG-CSF)] are now widely available. To date, biosimilar rhG-CSF has demonstrated a comparable quality, safety and efficacy profile to the originator product (filgrastim [Neupogen((R))], Amgen Inc., CA, USA) in the prevention and management of neutropenia. Biosimilar rhG-CSFs have also been used to induce peripheral blood stem cell (PBSC) mobilization in patients undergoing autologous stem cell transplantation (AHSCT). The authors have examined the effectiveness of a biosimilar rhG-CSF (Zarzio((R)), Sandoz Biopharmaceuticals, Holzkirchen, Germany) in two retrospective studies across two medical centers in Hungary. METHODS: In Study 1, 70 patients with hematological malignancies scheduled to undergo AHSCT received chemotherapy followed by biosimilar rhG-CSF (2 x 5 mug) for facilitating neutrophil, leukocyte, and platelet engraftment. In study 2, 40 additional patients with lymphoid malignancies and planned AHSCT received chemotherapy followed by biosimilar rhG-CSF for PBSC mobilization. The effectiveness of treatment was assessed by the average yield of cluster of differentiation (CD) 34+ cells and the number of leukaphereses required. RESULTS: In Study 1 (patients undergoing AHSCT), the median age was 56 years and most patients were male (60%). The conditioning regimens were mainly high-dose melphalan (n = 41) and carmustine (BiCNU((R)), Bristol-Myers Squibb, NJ, USA), etoposide, cytarabine and melphalan BEAM (n = 21). Median times to absolute neutrophil and leukocyte engraftment were 9 (range 8-11 days) and 10 (8-12) days, respectively. Median time to platelet engraftment was 10.5 days (7-19 days). In Study 2, the patients' median age was 54 years and the majority (57.5%) were female. The median time interval between day 1 of mobilizing chemotherapy and first leukapheresis was 12 (9-27) days. In the autologous PBSC grafts, the median number of CD34+ cells harvested was 5.2 x 10(6)/kg (2.22-57.07 x 10(6)/kg). The median yield of CD34+ cells per leukapheresis product was 2.47 x 10(6)/kg. In total, 58 leukaphereses were performed in 40 successfully harvested patients. CONCLUSIONS: In line with previous studies with originator rhG-CSF, the findings of this study indicate that biosimilar rhG-CSF following AHSCT is effective and generally well tolerated in the engraftment setting. In addition, biosimilar rhG-CSF is comparable to the originator rhG-CSF in terms of kinetics of PBSC mobilization and yield of CD34+ cells. In conclusion, the authors have demonstrated that the use of biosimilar rhG-CSF is effective and safe in autologous PBSC mobilization and engraftment after AHSCT.

Prostacyclin (PGI2) and β-carotene have a key role in gastric mucosal defence against endogenous or exogenous noxious agents. Prostacyclin has appreciable protective effects on the gastrointestinal (GI) mucosa, while β-carotene (as one of the retinoid compounds) has oxyradical scavenging properties.

Karadi O, Bodis B, Kiraly A, Abdel-Salam OME, Sutō G, Vincze A, Mozsik Gy. Surgical vagotomy enhances the indomethacin-induced gastrointestinal mucosal damage in rats. Inflammopharmacology. 1994;2:389-399.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant hereditary disease characterized by mucocutaneous pigmentation, gastrointestinal hamartomatous polyposis and an increased risk for the development of gastrointestinal and extra-gastrointestinal malignancies.Five generations of two PJS families (21-21 patients) were analyzed to summarize the clinical appearance of the disorder by interview, physical examination, laboratory and imaging studies.Phenotypic variability was observed in PJS both in and between families. In family "A" 13 people were diagnosed as being affected, all of them had melanin spots at birth and the first presenting clinical symptom was colicky abdominal pain (median age 12 years, range: 2-35) resulting in 14 laparotomies in 9 of the affected persons. 4/13 patients died from small-bowel ileus (median age 7 years, range 2-31), 2/13 from GI cancer (median age 54 years). In family "B" 7 patients were documented as being affected. The first features were also abdominal cramps (at age 22). The main causes of death were gynaecological (1/5) and GI malignancies (4/5) at advanced age, no one died in ileus.The results based on the analysis of the two families suggest that PJS is not a benign disease. It is difficult to predict the outcome of the disorder regarding the variable expression and incomplete penetrance. Therefore we emphasize the importance of checking the pedigree, finding out the leading symptom in the family; hemoccult test and routine lab studies should be carried out at every affected individual. If clinical signs and symptoms are present we recommend to perform the complete diagnostic protocol and a yearly follow-up by a gastroenterologist familiar with PJS focusing on the leading symptoms.

Retinoids prevent chemically induced gastric mucosal damage without inhibiting gastric acid secretion (”nutritional gastric cytoprotection”). The gastroprotective effects of retinoids do not depend on 1) vitamin A activity; 2) number of unsaturated double bonds; 3) the presence of a characteristic chemical structure of their terminal components; however, they depend on 1) intact vagal nerve and 2) adrenals in experimental animals. The gastric cytoprotective effect of retinoids produces a dose-dependent inhibition of ATP-transformation into ADP. It also increases the transformation of ATP into cAMP. Other features of these gastric cytoprotective effects of retinoids include: 1) The retinoid-induced gastric mucosal protection differs from that of PGs; 2) The cAMP is an intracellular signal in the development of gastric mucosal damage produced by chemicals (e.g., ethanol, HCl, indomethacin) and in the protection of gastric mucosa induced by retinoids (but not by PGs); 3) The gastric mucosal protection induced by retinoids and gastric mucosal permeability can be separated in time. The existence of gastric mucosal protection can be demonstrated in healthy persons (against indomethacin treatment), in patients with gastric ulcer (GU) and duodenal ulcer (DU) without any inhibition of gastric acid secretion. The serum levels of vitamin A and zeaxanthin were significantly decreased in patients with chronic gastrointestinal (GI) inflammatory diseases (e.g., terminal ileitis, ulcerative colitis), colorectal polyposis, and different (e.g., esophageal, gastric, pancreatic, hepatocellular and colorectal) malignant diseases. The serum levels of vitamin A provitamins were unchanged and their GI mucosal protective effects do not depend on vitamin A activity. Conclusions: 1) Abundant experimental and human observations clearly proved the defensive role of retinoids in the GI tract; 2) There is a correlation between the a) scavenger properties of retinoids vs. intact vagal nerve; b) scavenging properties vs. intact adrenals. 3) The GI mucosal protective effect of retinoids is correlated with biochemical changes in the GI mucosa.

Intragastric (ig) administration of 96% ethanol (EtOH, non-acid-dependent model) and 0.6 mol/L HCl (acid-dependent model) produces acute mucosal lesions in the rat stomach.

Peptic ulceration including acute erosions is a multifactorial disease involving well-known factors such as trauma, stress, sepsis, hemorrhagic shock, burns, pulmonary and liver diseases1–9 and drugs such as reserpine10, epinephrine11–13, nonsteroidal antiinflammatory drugs7, steroids and other chemicals14.