URINARY BLADDER CANCER RECURRENCE AND EXPRESSION OF LYNCH AND HER MARKERS: SEARCHING FOR IMMUNOHISTOCHEMICAL PATTERNS AMONG 113 TUMORS FROM 33 PATIENTS.

The aim was to identify immunohistochemical (IHC) markers able to predict recurrence of urinary bladder tumors. The method of multivariate adaptive regression splines (MARS) was applied to IHC data of 33 patients with urinary bladder cancer that relapsed one to six times (24 male and nine female, age 57-87 years). The MARS analysis was used to predict the total number of recurrences and the Ki-67 value by nine IHC markers (epidermal growth factor receptor (EGFR), HER2, HER3, E-cadherin, Ki-67, MLH1, MSH2, MSH6 and PMS2). Data were divided as initial tumors, first and subsequent recurrences, and tumors that relapsed within nine months of previous surgery or later. The IHC markers were semiquantitatively classified into four groups, as follows: 0 means no positive cells; 1, 10% of positive cells; 2, 11%-30% of positive cells; and 3, 31%-100% of positive cells. In predicting the overall number of recurrences, as a surrogate marker of tumor biology, the R2 value for all tumors was 0.423, for initial tumors 0.686, for first recurrence 0.700, and for subsequent recurrences only 0.233. The key predictors for initial tumors were HER2 and MSH2, while for the first recurrence it was EGFR. For quick recurrences (within nine months), the R2 was 0.474 with EGFR and HER3 as predictors, while for slow recurrences R2 was 0.640 due to EGFR and PMS2. In predicting the Ki-67 value of that tumor, the R2 value for all tumors was 0.300, for initial tumors 0.262, for first recurrence 0.360, and for subsequent recurrences only 0.533. The key predictors for first recurrences were EGFR and MSH6, and for subsequent recurrences HER2, EGFR and all Lynch markers. The R2 was 0.266 for quick recurrences and 0.370 for slow recurrences. The finding of E-cadherin was not found relevant by any of these MARS models. In conclusion, the MARS results associated multiple IHC markers with the number of recurrences and with Ki-67 values. It is important that differences in predictive markers were found between initial tumors and first recurrences, and between quick and slow recurrences, thus suggesting that tumor biology is different among these subgroups regarding the total number of recurrences and Ki-67 values.

The renin-angiotensin system in COVID-19: Why ACE2 targeting by coronaviruses produces higher mortality in elderly hypertensive patients?

This renin-angiotensin system (RAS) interpretation is focused on differences in tissue dependence on RAS and on the topological hierarchy that allows mediators to act only on downstream tissues. Dependence of tissues on RAS: Tested by expectation maximization clustering of the RNA human tissue expression (https://biogps.org/). ACE and vasoconstrictive AT1R clustered with the prorenin receptor. ACE2 and dilatory MAS1 clustered with nine RAS-related genes, highly expressed in: Liver; Cardiac_Myocytes; Skeletal_Muscle; Uterus; Kidney; Lung; Small_Intestine; Smooth_Muscle. RAS and stress accumulation: While prorenin is active after binding to its receptor, binding of soluble renin increases its enzymatic activity several times. Increased renin secretion multiplies the overall capacity for producing Ang I, leading to hypertension and increased vascular resistance. Coronavirus infection and comorbidities: Cardiorespiratory failure during infection is linked to the previously altered RAS role in lungs and myocardium. Reduced vasodilation by ACE2 lead to vasoconstriction and suboptimal tissue perfusion patterns. Also see the video abstract here https://www.youtube.com/watch?v=Jf0Iped-Mws.

What Are the Health Risks of Eating Red Meat, and How Should We Assess Them?

This paper discusses possible mechanisms that might lead to misinterpretations of collected data and makes new evidence-based medicine (EBM) recommendations to oppose the previously accepted preventive measures, or treatment options. It is focused on the danger of the "red meat" consumption, and the question whether eating pungent food is good or bad for our health and finally whether the "bad luck" concept of getting several cancer types is valid or not. These three topics got and still have significant media attention. Several mechanisms are proposed as possible causes of these apparent conflicts. Some of them have already been recognized but sadly remained less known to medical readers and also to the general population. Also see the video abstract here https://youtu.be/owjoRXrNShA.

Was the Last Ice Age dusty climate instrumental in spreading of the three "Celtic" diseases (hemochromatosis, cystic fibrosis and palmar fibromatosis)?

Cystic fibrosis, hereditary hemochromatosis and palmar fibromatosis are often described as "Celtic", based on their contemporary prevalence. The former two are among genetically defined disorders that seem to provide survival advantages to heterozygote individuals, while severe health problems happen in homozygote mutation carriers. Although palmar fibromatosis has no defined mutations, its prevalence has been linked to the prevalence of Y-Chromosome Haplogroup I that expanded after the Last Ice Age, thus making th distribution of all three "Celtic" diseases dependent on the global climate from 40 to 8 Kya. During the Last Ice Age, the global climate was dry and dark due to dust-laden atmosphere (20-25 times more than today). It has been postulated that skin pigmentation was related to insolation, UV protection and skin synthesis of vitamin D, so when our ancestors moved to Eurasia, individuals with pale skin became advantageous. Deficiency of vitamin D has several health consequences and some of them have been proposed by other authors as important for the spreading of cystic fibrosis mutations: rickets/osteomalacia; susceptibility to diarrheal diseases and tuberculosis and salt induced arterial hypertension. The here proposed link is between vitamin D deficiency and the anaemia of chronic disease that might have facilitated spreading of the hemochromatosis mutation. It seems plausible that the risk of health problems in the offspring of close relatives might have resulted in social taboos of consanguinity in Eurasian protosocieties. Ancient steam bath rituals seem linked to lower incidences of cystic fibrosis in several European populations, thus suggesting health protection in an arid, dusty climate of the last glaciation, that made CFTR mutations in heterozygote carriers less advantageous.

Distribution of Ki-67 values within HER2 & ER/PgR expression variants of ductal breast cancers as a potential link between IHC features and breast cancer biology.

BACKGROUND: Unexpected differences in Ki-67 values among HER2 & ER/PgR defined subgroups were found. This study aims to detect possible subdivisions beyond the conventional breast cancer types. METHODS: One thousand one hundred eighty consecutive patients with invasive ductal breast carcinoma were included and distributed in 16 subgroups (four HER2 phenotypes (0+, 1+, 2+ and 3+) times four ER/PgR phenotypes). Complex distributions of Ki-67 values were tested by expectation maximization (EM) clustering. RESULTS: Pooled Ki67 values of all patients showed the presence of three EM clusters (defined as LMA-low mitotic activity, IMA-intermediate mitotic activity and HMA-high mitotic activity) with expected mean Ki-67 values of 1.17%, 40.45% and 77.79%, respectively. Only ER-PgR- tumors significantly dispersed in three clusters (29.75% tumors in LMA, 46.95% in IMA and 23.30% in the HMA cluster), while almost no detected HMA tumors were of ER + PgR+ or ER + PgR- phenotypes. Among 799 ER + PgR+ patients distribution in clusters was HER2 dependent (p = 0.000243), due to increased number of IMA HER2 3+ tumors on the expense of LMA HER2 3+ tumors (52 IMA out of 162 HER2 3+ patients versus113 IMA out of 637 HER2 < 3+ patients). This was not found among ER + PgR- patients (p = 0.186968). Among ER-PgR- patients, HER2 overexpression also increased number of IMA tumor, but by reducing the number of HMA tumors (p < 0.000001). Here, difference between HER2 absent (0+) and HER2 3+ patients was evident (10 HMA out of 125 HER2 3+ patients versus 42 HMA out of 103 HER2 0+ patients). CONCLUSIONS: Results suggest that distributions of breast cancers in three clusters of mitotic activity depend on different mechanisms for ER + PgR+ and ER negative tumors. Although HER2 overexpression increases number of IMA tumors in both settings, in the former it is done by reducing number of LMA tumors, while in the latter it reduces the number of HMA tumors. Mitotic activity of ER + PgR- tumors seems unrelated to the HER2 status, possibly as an indicator that ER dysfunctionality in cancers that lack PgR expression. Among ER negative tumors, the absence of HER2 (0+) might be as important as the HER2 overexpression.

[CANCER PATIENTS FOLLOW-UP ­ CROATIAN SOCIETY FOR MEDICAL ONCOLOGY CLINICAL GUIDELINES Part IV: planocellular head and neck cancer, oesophageal cancer, gastric cancer, colorectal cancer].

Treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not being based on prospective studies, yet on the expert's opinion of a precise oncological center or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures' algorithm in follow­up of oncological patients after primary treatment, in patients with planocellular head and neck cancer, oesophageal cancer, gastric cancer and colorectal cancer.

Similar Distributions of Dupuytren's Contracture and Y-Chromosome Haplogroup I Among Modern Europeans Suggest Simultaneous Spreading of These Traits Some 40 to 10 KYA.

A proposition is made that when two independent traits show similar regional patterns of incidence among modern European regions, a plausible expectation is that these two, otherwise unrelated traits, have simultaneously been spread by migration of our ancestors. As a potential example for the proposed concept, distribution of patients with Dupuytren's contracture is here compared with the reported European distribution of Y-Chromosome Haplogroup I, a genetic marker linked to the last glaciation period.

Are predictions of cancer response to targeted drugs, based on effects in unrelated tissues, the 'Black Swan' events?

Adverse effects of targeted drugs on normal tissues can predict the cancer response. Rash correlates with efficacy of erlotinib, cetuximab and gefitinib and onset of arterial hypertension with response to bevacizumab, sunitinib, axitinib and sorafenib, possible examples of 'Black Swan' events, unexpected scientific observations, as described by Karl Popper in 1935. The proposition is that our patients have individual intrinsic variants of cell growth control, important for tumor response and adverse effects on tumor-unrelated tissue. This means that the lack of predictive side effects in healthy tissue is linked with poor results of tumor therapy when tumor resistance is caused by mechanisms that protect all cells of that patient from the targeted drug effects.

Cystic fibrosis: model of pathogenesis based on the apical membrane potential.

A simple model of cystic fibrosis (CF) is proposed, based on the apical membrane (ApM) potential. The ApM of epithelial cells is highly permeable to sodium and activation of CFTRs makes it permeable to chloride. Calculated ApM potentials of cells with activated cystic fibrosis transmembrane conductance regulators (CFTRs) are between the sodium and chloride Nernst values and thus allow rapid absorption of both ions in exocrine glands. In CF patients the potential is near the sodium Nernst value and thus more salt is left in the ducts. Simulation predicts that the sodium driving force increases more than 3.5 times if the ApM permeability for Cl- increases from 5-94% of the sodium permeability. In pancreatic ductal cells basolateral sodium bicarbonate cotransporters (pNBC1) allows influx of bicarbonates with sodium. Bicarbonates are exchanged for intraductal chloride by anion exchanger 1 (AE1) in the ApM. Activated CFTRs let some chloride to leak back to ducts, followed by water that dilutes ductal proteins. Replenished intraductal chloride allows more bicarbonate secretion. In CF patients, pancreatic water and bicarbonate secretion is limited by the intraductal chloride pool.

Hypothesis: Possible respiratory advantages for heterozygote carriers of cystic fibrosis linked mutations during dusty climate of last glaciation.

This paper puts forward a new hypothesis to interpret the high carrier frequency of CFTR mutations in individuals of European descent. The proposed heterozygote advantage factor is related to the specific climate conditions in Europe during the last 50 ky that might have heavily compromised the respiratory function of our ancestors in Eurasia. A large part of the last 50 ky was cold, and the coldest period was the Last Glacial Maximum (LGM) (26.5 to 19 kya). The global climate was dry with a dust-laden atmosphere (20 to 25 times more dust than the present level). High levels of atmospheric dust started more than 40 kya and ended less than 10 kya. Secretion of airway fluid is usually related to the submucosal tissue hydration, while salt reabsorption relies on activation of CFTRs that allow ENaCs to absorb salt and water. The water loss by evaporation depends on the air humidity and flow rate. Salt accumulation in the mucus is normally prevented by reabsorption of Na(+) and Cl(-) by epithelial cells if the presence of functional CFTRs is normal. If one gene for CFTR is mutated, the number of functional CFTRs is reduced and this limits the capacity of salt reabsorption by epithelial cells. This means that evaporation makes the airway fluid more hypertonic, and osmotic forces bring more water from the interstitial space, thus leading to a new balance in mucosal fluid traffic. Increased osmolarity and volume of airway fluid can be more moveable in cases when evaporation and dust exposure is increased. If both CFTR genes are mutated, low number of functional CFTRs diminishes salt resorption of epithelial cells. Salt accumulated in the mucous fluid within respiratory ducts, as previously described. The hypertonic ductal content forces more water and some electrolytes to enter the airway fluid from the interstitial fluid, and evaporation leads to further concentration of thick immobile mucus. The proposed interpretation is that CFTR mutations have spread among our ancestors that roamed the central Eurasia after the LGM. The heterozygote individuals might have benefitted from the limited water resorption in their respiratory mucosa that allowed improved airway cleansing.

A model of immunohistochemical differences between invasive breast cancers and DCIS lesions tested on a consecutive case series of 1248 patients.

BACKGROUND: A previous theoretic model (Tumour Biol 2013;34:1-7.) that breast tumor types differ in the relative rate of tissue invasion was elaborated and developed on a consecutive case series. METHOD: Histologic data of 68 ductal breast cancer in situ (DCIS) and 1180 invasive ductal cancer (IDC) patients were collected and analyzed. RESULTS: ER+PgR- phenotype was more common in Luminal B2 than among the pooled Luminal A&B1 (p = 0.0002), and more frequent in Luminal B1 than in Luminal A (p = 0.0167). The same phenotype was associated with the age older than 54 years in Luminal B1 and in B2 patients. HER2 type cancers were more frequent in older patients (p = 0.0038).Tumor progression from DCIS to IDC was found 39% faster than the average in Luminal B1 tumors, supporting the clinical importance of this tumor type. A rare combination of low Ki-67 in HER2 type cancers (only 14% of HER2 type cancers) showed very slow transition to IDC (occurring at only 53.55% of average progression rate), while triple-negative cancers progressed faster than the average, despite Ki-67 value (104.63% for low and 114.27% for high Ki-67 tumors).In three tumor types with positive steroid receptors the ER+PgR- phenotype showed slower IDC transition than the ER+PgR+ phenotype of the same tumor type (difference in progression rate was 38% for Luminal A, 46% for Luminal B1 and 67% for Luminal B2 with Ki67 > 14%).Triple-negative tumors in younger patients exceeded the expected average progression rate by 24%, while in HER2 type tumors, the rate of tissue invasion was in younger patients 20% lower than the expected value. CONCLUSIONS: The relative rate of tissue invasion differed substantialy among our patients. Differences depended on tumor types, steroid expression phenotypes and age. The dysfunctional ERs in the ER+PgR- phenotype showed slower rates of tissue invasion, suggesting that ligand binding to functional breast tumor ERs, beside promoting the PgR expression, possibly also promotes tumor transition to the invasive phase.In triple-negative tumors, an age dependent premenopausal mechanism possibly acted as an accelerator of tissue invasion, while faster tissue invasion by HER2-overexpressed tumors in older patients possibly depended on an unidentified mechanism that takes more time to be acquired, so it was less present in premenopausal patients.

GISTs' classifications in predicting aggressive behavior: a single institution experience.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. When making treatment plan it is very important to make proper tumor aggressiveness estimation. Traditionally, the best prognostic factors are tumor size and number of mitoses. The aim of this study was to define which GIST classification (Amin's or Newman's classification or Fletcher's Consensus Criteria) is the most significant determining prognosis and has the strongest impact on survival. This study included 63 GIST patients whose tumor specimens were evaluated by standard histopathological methods and classified based on histological assessment of malignant behavior to the three different systems. Comparison of those classification systems was done and none of them was proven to be statistically significantly better in predicting overall survival and probability of lethal outcome. We conclude that all three classifications are comparable in prediction of malignant behavior. The worst prognostic factor is existence of metastases at the time of disease diagnosis.

Model of tumor-associated epigenetic changes of HER2, ER, and PgR expression in invasive breast cancer phenotypes.

This theoretic paper is an attempt to apply the epigenetic progenitor model of human cancer origin, proposed by Feinberg et al. (Nat Rev Genet 7:21-33, 2006), to the reported phenotype features of invasive breast cancer. The model is based on the idea that expression of estrogen receptors (ER), progesterone receptors (PgR), and HER2 molecules in breast tumors is either remnants of the tissue stem cell from which the tumor has developed or a newly acquired tumor-associated epigenetic feature. HER2 overexpression is considered as an example of the tumor-associated epigenetic changes. The model makes a simple distinction regarding the possible types of ER and PgR expression: the "functional" steroid hormone receptors are inherited from pretumoral tissue stem cells, while the "dysfunctional" steroid hormone receptors are acquired during tumorigenesis from initially ER-PgR-negative cells. In the former, estrogen binding increases the PgR expression while progesterone binding decreases the expression of ER and PgR. Since the estrogen-dependent PgR expression works only in cells with functional ERs, the expected share of tumors with functional ER and PgR receptors is in the model calculated as the squared probability of expressing the PgRs. Reported data from various trials are pooled together to find out phenotype shares (ER+PgR+ makes 62.03 %, ER+PgR- 16.43 %, ER-PgR+ 3.06, and ER-PgR- 18.48 %). By applying the model on these shares, the proposed share of tumors with the functional ER+PgR+ phenotype was 38.48 %, while the share of tumors with the dysfunctional ER+PgR+ was 23.55 %. The presented model suggests that both luminal A and luminal B tumor types are heterogeneous regarding the steroid receptor expression. Some tumors have functional and some have dysfunctional steroid receptors. If these predicted subgroups exist, their detection in the clinical practice might substantially improve treatment options, particularly in the premenopausal setting.

In search of triple-negative DCIS: tumor-type dependent model of breast cancer progression from DCIS to the invasive cancer.

This paper is based on the idea that ductal breast cancer in situ (DCIS) precedes the invasive breast cancer (invBC), although the triple-negative invBCs almost lack their DCIS precursor. Reported incidences of breast tumor types in DCIS and in invasive BCs suggest that probabilities of tumor progression might differ among tumor types, and these differences can have some impact on our patients. Reported data from several papers on incidences of the four breast tumor types-luminal A, luminal B, HER2, and triple negative-are used to compare tumor-type incidences for DCIS and for the invasive BC. The pooled distributions differed (Χ (2) = 97.05, p < 0.0001), suggesting a strong selection pressure that reduces the number of triple-negative DCIS lesions at the time of breast tumor diagnosis. Reported shares of DCIS in all newly diagnosed breast cancers range in large screening trials from 9 to 26 %, so in making a population model, three values are arbitrarily chosen: one DCIS out of ten breast cancers (the 10 % share), one DCIS out of seven breast cancers (one seventh or the 14.3 % share), and one out of five (the 20 % share). By using these shares and the pooled data of tumor-type incidences, values are calculated that would be expected from a hypothetical population in which types of DCIS and invasive BC are distributed accordingly to the reported incidences. The model predicts that the shares of breast cancer tumor types in the modeled population (DCIS plus invasive BCs) are 39 % for luminal A, 20 % for luminal B, 11 % for HER2 positive, and 30 % for the triple-negative cancers. Some 59 % of all breast tumors are expected to be hormone receptor positive, and HER2 to be overexpressed in 31 %. Simulated probabilities of tumor progression were used to calculate the number of tumor progression t(1/2) that has passed before the time of diagnosis. Calculated relative t(1/2) durations in the modeled population suggest that the triple-negative DCIS cases were fastest in tumor progression, three times faster than the HER2-positive tumors and near twice as fast as luminal A. Luminal A is the model slower than luminal B DCIS, suggesting that although their progression depends on estrogen exposure, HER2 overexpression in luminal B tumors adds some speed in tumor progression. The model results suggest that quick tumor progression might be the main feature of the triple-negative breast tumors, leading to seldom triple-negative DCIS at the time of breast cancer diagnosis. Applying approach of the presented model to the real data from a well-defined population seems warranted.

Can estrogen receptor overexpression in normal tissues due to previous estrogen deprivation explain the fulvestrant efficacy in breast cancer therapy?

Fulvestrant is a down-regulator of estrogen receptors (ERs) with still evolving optimal dosage for ER-positive breast cancer patients. The CONFIRM phase III trial in women with advanced breast cancer proved fulvestrant 500-mg to be associated with a longer time till progression (TTP) than the 250-mg schedule. Detailed results suggest that the fulvestrant in both schedules depended on the previous endocrine therapy. All complete responses and the only significant TTP difference between the two schedules was found among women previously treated with tamoxifen (TAM) and not in women after aromatase inhibitors (AIs). Noting that TAM competes with estrogen binding to ERs is important, so the optimal TAM dosage produces drug concentrations comparable to concentrations of available ER ligands. All AIs diminish production of the main ER ligand, so the optimal AI dosage depends on the overall pool of aromatase molecules in the body. Both treatments are not directly related to the pool of available ERs in the body. Here proposed interpretation is that estrogen deprivation due to years of endocrine breast cancer therapy increases ER expression in breast cancer cells and in other healthy estrogen target tissues. The breast cancer exposure to fulvestrant depends on the presence of all ERs in the body. Only when this overall pool is sufficiently saturated with fulvestrant, we can expect to achieve some breast cancer response due to down-regulation of ER in cancer tissue. The CONFIRM data suggest that among patients switching from TAM to fulvestrant, only the 500-mg schedule could down-regulate the moderately enlarged total body ER pool and thus induce breast cancer regression. In patients switching from previous AI treatments, both 250 and 500-mg schedules were unable to prolong the TTP, suggesting that in both doses, fulvestrant showed no efficacy since the overall ER pool was more enlarged after AIs. Fulvestrant might be more effective before TAM and AIs, in the first line endocrine therapy of metastatic breast cancer, since an unaltered ER pool in normal tissues is expected in this setting.

A phase plane graph based model of the ovulatory cycle lacking the "positive feedback" phenomenon.

When hormones during the ovulatory cycle are shown in phase plane graphs, reported FSH and estrogen values form a specific pattern that resembles the leaning "&" symbol, while LH and progesterone (Pg) values form a "boomerang" shape. Graphs in this paper were made using data reported by Stricker et al. [Clin Chem Lab Med 2006;44:883-887]. These patterns were used to construct a simplistic model of the ovulatory cycle without the conventional "positive feedback" phenomenon. The model is based on few well-established relations:hypothalamic GnRH secretion is increased under estrogen exposure during two weeks that start before the ovulatory surge and lasts till lutheolysis.the pituitary GnRH receptors are so prone to downregulation through ligand binding that this must be important for their function.in several estrogen target tissue progesterone receptor (PgR) expression depends on previous estrogen binding to functional estrogen receptors (ER), while Pg binding to the expressed PgRs reduces both ER and PgR expression.Some key features of the presented model are here listed:High GnRH secretion induced by the recovered estrogen exposure starts in the late follicular phase and lasts till lutheolysis. The LH and FSH surges start due to combination of accumulated pituitary GnRH receptors and increased GnRH secretion. The surges quickly end due to partial downregulation of the pituitary GnRH receptors (64% reduction of the follicular phase pituitary GnRH receptors is needed to explain the reported LH drop after the surge). A strong increase in the lutheal Pg blood level, despite modest decline in LH levels, is explained as delayed expression of pituitary PgRs. Postponed pituitary PgRs expression enforces a negative feedback loop between Pg levels and LH secretions not before the mid lutheal phase.Lutheolysis is explained as a consequence of Pg binding to hypothalamic and pituitary PgRs that reduces local ER expression. When hypothalamic sensitivity to estrogen is diminished due to lack of local ERs, hypothalamus switches back to the low GnRH secretion rate, leading to low secretion of gonadotropins and to lutheolysis. During low GnRH secretion rates, previously downregulated pituitary GnRH receptors recover to normal levels and thus allow the next cycle.Possible implications of the presented model on several topics related to reproductive physiology are shortly discussed with some evolutionary aspects including the emergence of menopause.

Arterial hypertension due to fructose ingestion: model based on intermittent osmotic fluid trapping in the small bowel.

Based on recently reported data that fructose ingestion is linked to arterial hypertension, a model of regulatory loops involving the colon role in maintenance of fluid and sodium homeostasis is proposed.In normal digestion of hyperosmolar fluids, also in cases of postprandial hypotension and in patients having the "dumping" syndrome after gastric surgery, any hyperosmolar intestinal content is diluted by water taken from circulation and being trapped in the bowel until reabsorption. High fructose corn sirup (HFCS) soft drinks are among common hyperosmolar drinks. Fructose is slowly absorbed through passive carrier-mediated facilitated diffusion, along the entire small bowel, thus preventing absorption of the trapped water for several hours.Here presented interpretation is that ingestion of hyperosmolar HFCS drinks due to a transient fluid shift into the small bowel increases renin secretion and sympathetic activity, leading to rise in ADH and aldosterone secretions. Their actions spare water and sodium in the large bowel and kidneys. Alteration of colon absorption due to hormone exposure depends on cell renewal and takes days to develop, so the momentary capacity of sodium absorption in the colon depends on the average aldosterone and ADH exposure during few previous days. This inertia in modulation of the colon function can make an individual that often takes HFCS drinks prone to sodium retention, until a new balance is reached with an expanded ECF pool and arterial hypertension. In individuals with impaired fructose absorption, even a higher risk of arterial hypertension can be expected.

Can incidence of depression in women be linked to estrogen dependent secretion of various hormone binding proteins?

This paper describes a possible framework of hormones and their binding proteins (BPs) that might be responsible for the increased incidence of depression in women, including postnatal depression. It is based on three reported facts: Increased cortisol exposure reduces growth hormone (GH) secretion. Cortisol and GH show opposite effects on mood. Liver secretion of various hormone binding proteins is increased under estrogen exposure. If we accept that pure cortisol exposure leads to depressive mood, while simultaneous brain exposure to cortisol and an anabolic (growth hormone or somatomammotropin) is less mood affecting, the occurrence of depression an be more likely in persons: with altered sleep patterns and thus reduced GH secretion, in individuals with increased chronic cortisol exposure (any individual under repeated or sustained stress, older individuals with stressful memories, etc.). The proposed mechanism can be enhanced in women of reproductive age through increased transcortin and GH BP pools due to estrogen action on liver. A particularly vulnerable phase seems to be the early postnatal period, when sudden discontinuation of somatomammotropin anabolic actions might lead to postnatal depression that takes weeks or months to resolve, until the GH/cortisol circadian rhythm normalization.

Human adiposity, longevity and reproduction features as consequences of population bottlenecks.

A model of the origin of modern humans through several population bottlenecks caused by glacial cycles and cold-arid periods was used as a frame for describing occurrence of unique physiological characteristics. Occurrence of regular evening food sharing among the hominid group members improved their chances of finding food the next day. It allowed slow emergence of a gracile and energy efficient phenotype. Improving chances of group survival in the harsh environment included these traits: - The menstrual cycle occurrence in the common ancestor of human and great apes. - Single pregnancies only in women with sufficient fat reserves. Ovulations stop during the food shortage seasons, or longer periods of starvation and during lactation. - Women prone to obesity sooner become pregnant, passing the obesity trait as an advantage. - Seldom pregnancies separated by several years of anovulation made a strong pressure toward the longevity of women and man. - Menopausis improved the group survival through preventing pregnancy of women to old to deliver and raise children without significant risks. The modern times food abundance results in high incidences of adiposity, diabetes and metabolic syndrome. Continuos ovulations from puberty to menopausis except during seldom pregnancies and lactations is considered responsible for the occurrence of estrogen induced breast and endometrial cancers. The combination of longevity with decades of androgen secretion is the main cause of prostate cancer.