Responsible Substance Research Articles

Robert Tigerstedt and the Discovery of Renin.

The year 2022 marks the 125th anniversary of the discovery of the first element of the renin-angiotensin-aldosterone system. The importance of this event on the further development of nephrology, cardiology, and endocrinology left us compelled to reminisce about it and its main author, Robert Tigerstedt (1853-1923), who was one of Scandinavia's most famous scientists. He studied medicine at the University of Helsinki, Finland. His doctoral dissertation On the Mechanical Stimulation of the Nervous System and 10 other original publications made him famous among the neurophysiological community. From 1881, he worked in the Physiology Department at Karolinska Institute, Stockholm, where he created a modern laboratory and became a professor at age 33 years. After meeting Carl Ludwig in Leipzig, he became interested in central blood circulation. In 1886, with Per Bergman, he started a series meticulously performed experiments with extracts of the rabbit kidney cortex, which, when injected into other rabbits, increased their blood pressure. The hypothetical responsible substance was called renin. The results were presented at the International Congress of Medicine in Moscow in 1887. Forty years later, Harry Goldblatt confirmed Tigerstedt's theory that "the substance which comes from kidneys increases the blood pressure." After he returned to Finland in 1901, Tigerstedt headed the Physiology Institute in Helsinki. His further activities included scientific work, teaching, and socially oriented issues like healthy nutrition and conditions in prison camps. He was also interested in the history of medicine and was a member of the Nobel Committee. His Textbook of Human Physiology was published in numerous editions in many languages. He also authored the renowned Textbook of Physiological Methodology and Physiology of Circulation. Tigerstedt published over 200 scientific papers and was an honorary doctor at many universities. He was known for his strong personality, critical judgment, idealism, humor, and warm heart.

Promoting Healthy Attitudes and Behaviors in Youth Who Experience Homelessness: Results of a Longitudinal Intervention Study

PurposeThe aim of this study is to determine the effectiveness of a brief intervention to promote responsible substance use and safe sex behaviors in youths experiencing homelessness (YEH). MethodsDesign: A Solomon four-group (double randomized controlled trial) longitudinal design with repeated measures (3- and 6-month follow-ups) was used in drop-in centers for YEH in Austin, Texas and Columbus, Ohio from which 602 youths, 18-24 years-old (M = 21 ± 1.8), 50% white; 69.9% heterosexual were recruited. A manualized one-on-one intervention consisted of six modules delivered via laptop computers. Modules focused on communication, goal-setting, substance use refusal, safe sex behaviors, enhanced psychological capital (hope, optimism, resilience, self-efficacy, gratitude), and life satisfaction. Valid and reliable measures of hope, optimism, future time perspective, resilience, social connectedness, gratitude, condom intention, self-efficacy for safe sex, safe sex behaviors, self-efficacy for substance use refusal, and life satisfaction were used to collect data for which three hypotheses were tested, using intent to treat, with multi-level modeling (R). ResultsThe analysis showed partial support for all hypotheses: (1) post-test outcomes were greater than pretests; (2) intervention group outcomes were greater than control group measures; and (3) significant effects for pretesting. YEH in Ohio completed significantly more sessions than YEH in Texas (p = .001), but took significantly longer to complete all six sessions (p = .001). DiscussionThis brief intervention had significant effects on YEH to promote healthy attitudes and behaviors that merit further testing in larger samples.

'Colouring' wipes phenomenon: a peculiar skin pigmentation induced by ascorbic acid observed during lockdown.

SummaryDuring the SARS‐CoV‐2 (COVID‐19) pandemic, an unusual outbreak of yellow–brown pigmentation on the skin of children was reported. Because of the restrictions on movement promulgated during the lockdown, most consultancies were performed using teledermatology. Data concerning personal care products and application of topical substances were collected, which revealed use of the same brand of wipes for all patients. A liquid chromatography–mass spectrometry analysis was performed to compare the components of the wipes before and after the observation of the pigmentation, in order to detect the responsible substance. This analysis revealed a level about 10‐fold higher than normal of ascorbic acid and its oxidation products (dehydroascorbic acid and L‐threonic acid) in the wipes associated with the pigmentation. These ‘colouring wipes’ represent a peculiar but harmless phenomenon that highlights the importance of careful questioning about personal care products used by patients.

High-performance thin-layer chromatography in combination with a yeast-based multi-effect bioassay to determine endocrine effects in environmental samples.

Effect-directed analysis (EDA) that combines effect-based methods (EBMs) with high-performance thin-layer chromatography (HPTLC) is a useful technique for spatial, temporal, and process-related effect evaluation and may provide a link between effect testing and responsible substance identification. In this study, a yeast multi endocrine-effect screen (YMEES) for the detection of endocrine effects is combined with HPTLC. Simultaneous detection of estrogenic, androgenic, and gestagenic effects on the HPTLC plate is achieved by mixing different genetically modified Arxula adeninivorans yeast strains, which contain either the human estrogen, androgen, or progesterone receptor. Depending on the yeast strain, different fluorescent proteins are formed when an appropriate substance binds to the specific hormone receptor. This allows to measure hormonal effects at different wavelengths. Two yeast cell application approaches, immersion and spraying, are compared. The sensitivity and reproducibility of the method are shown by dose-response investigations for reference compounds. The spraying approach indicated similar sensitivities and higher precisions for the tested hormones compared to immersion. The EC10s for estrone (E1), 17β-estradiol (E2), 17α-ethinylestradiol (EE2), 5α-dihydrotestosterone (DHT), and progesterone (P4) were 95, 1.4, 10, 7.4, and 15pg/spot, respectively. Recovery rates of E1, E2, EE2, DHT, and P4 between 88 and 120% show the usability of the general method in combination with sample enrichment by solid phase extraction (SPE). The simultaneous detection of estrogenic, androgenic, and gestagenic effects in wastewater and surface water samples demonstrates the successful application of the YMEES in such matrices. This promising method allows us to identify more than one endocrine effect on the same HPTLC plate, which saves time and material. The method could be used for comparison, evaluation, and monitoring of different river sites and wastewater treatment steps and should be tested in further studies.

A Molecular Description of Superconductivity of Sulfur Hydride and Related Systems under High-Pressure Conditions

It has been shown that the recently discovered sulfur trihydride (H3S) can be considered as a superconductor with a transition temperature Tc of 203 Kelvin (K) at 155 GigaPascals (GPa). This is the highest Tc value reported for any superconductor. The established superconductivity occurs via the formation of a molecular system with sulfur atoms arranged on a body-centered cubic lattice. It has been generally accepted that the high Tc value is the result of an efficient electron-phonon interaction. The responsible substance formed by H2S under high pressure, may be considered as a compound with H3S stoichiometry creating an impressive network with hydrogens. We will focus on the hydrogen bonding between sulfur and hydrogens demonstrating a symmetrical arrangement. The geometry of the individual radical compound in relation to corresponding systems will be discussed. Ab initio calculations based on a linear three-center two-, three- and four-electron type of bonding clearly visualized in combination with the dynamics of the Van’t Hoff concept, as described by us in various papers, give a good description of this exclusive network. We also discuss the superconductivity of related phosphorus hydrides and focus on the stability and geometrical differences with respect to the H3S system. These differences are significant, demonstrating the diversity in various structures in showing superconductivity.

In vitro elucidation of the metabolic profile of the synthetic cannabinoid receptor agonists JWH-175 and JWH-176

The continuing rise of synthetic cannabinoids consumption remains an analytical challenge. Proof of the intake of these substances is crucial when it comes to driving under the influence of illicit drugs, proof of abstinence after revocation of a driving license, mandatory workplace drug screenings, or judgement of legal culpability of a criminal suspect. Furthermore, in clinical cases of intoxication, the identification of the responsible substance is essential. Because of the short half-life time and the extensive metabolism of synthetic cannabinoids, blood is not the optimal matrix for the verification of elapsed consumption. The parent substance appears in urine only for a very short time period after intake. Therefore, it is crucial to include the metabolites of such substances in the analytical screening strategies. In this work we elucidated the in vitro metabolism of synthetic cannabinoids belonging to the naphthylmethylindole- and the naphthylmethylindene family. Low- and high-resolution mass spectrometry experiments have been performed to identify the formed metabolites. In total, 27 phase I metabolites of JWH-175 and eight of JWH-176 were identified. The obtained metabolic pattern of JWH-175 and JWH-176 can be used to supplement existing screening methods to be able to prove the intake of the investigated synthetic cannabinoids. To our knowledge this is the first report describing the metabolites of JWH-175 and JWH-176.

Lambertellin system, the mechanism for fungal replacement of Monilinia fructigena with Lambertella corni-maris without competitive inhibition on agar media

The ‘Lambertellin system’ was disclosed which rationally explains the fungal replacement (mycoparasitism) of Monilinia fructigena (M. f., the host) with Lambertella corni-maris (L. corni-maris, the parasite) without competitive inhibition in the simultaneous incubations on agar media. The ‘Lambertellin system’ involves; (a) L. corni-maris secretes nontoxic lambertellols (1, 2) as the diffusible precursors of the authentic responsible substance 3 regardless of existence of the host M. f.; (b) In the absence of the host, the environment around the parasite is kept under neutral condition, and both 1 and 2 are readily transformed into 3; (c) Lambertellin (3) inhibits not only the host but also the parasite. The parasite degrades 3 for detoxification; and (d) Upon the host M. f. approaching closely to the area where the parasite inhabits, the environment around the parasite becomes acidic to stabilize 1 and 2, which gives them a chance to diffuse into the host area. Then these are gradually transformed into 3 to inhibit the host without damaging the parasite. This mechanism also accords with the progress of ‘Natsu-Nenju’ disease on apple fruits, which is known to be a mysterious phyto-disease because of two unique stages of its lifecycle, anamorphic (asexual) and teleomorphic (sexual). The ‘Lambertellin system’ would be categorized as a novel class of alleropathies.

The Role of the Family in Promoting Responsible Substance Use in Adolescence

The aim of this study was to examine the role of family dimensions in tobacco, alcohol, and cannabis use among adolescents. Furthermore, we investigated how demographic variables (adolescents’ gender and age) influence substance use and moderate the relationship between family dimensions and substance use. The sample consisted of 14,825 adolescents aged 13–14, 15–16, and 17–18 who participated in the 2006 edition of the Health Behaviour in School-aged Children (HBSC) study in Spain. The HBSC-2006 questionnaire included demographic variables (gender and age), substance use variables (tobacco, alcohol, and cannabis use), and family dimensions (parental affection, parental promotion of autonomy, family activities, adolescent disclosure, parental solicitation, and parental knowledge). The results indicated that adolescent disclosure, family activities, and parental knowledge had a significant effect on substance use. Specifically, maternal variables were shown to be slightly more relevant than paternal variables. Additionally, substance use was higher in older adolescents than in younger adolescents, and boys smoked less than girls. The discussion focused on how family dimensions promoted responsible substance use in adolescence.

Black tattoo inks are a source of problematic substances such as dibutyl phthalate

Tattooing has recently become increasingly popular. Using tiny needles, tattooists place the tattoo ink in the dermis along with numerous unknown ingredients. Most tattoos consist of black inks, which are predominantly composed of soot products (carbon black with polycyclic aromatic hydrocarbons). Black tattoos cause skin problems, including allergic reactions, but the responsible substance frequently remains unknown. We applied gas chromatograph-mass spectrometry analysis to search for hazardous compounds in 14 different commercially available black tattoo ink samples. The analysis revealed that all inks contained the softener substance dibutyl phthalate (0.12-691.2 µg/g). Some of the inks contained hexachloro-1,3-butadiene (0.08-4.52 µg/g), metheneamine (0.08-21.64 µg/g), dibenzofuran (0.02-1.62 µg/g), benzophenone (0.26-556.66 µg/g), and 9-fluorenone (0.04-3.04 µg/g). The sensitizing agent dibutyl phthalate acts directly on keratinocytes and can drive Th2 responses following skin exposure via induction of thymic stromal lymphopoietin gene expression. Hexachloro-1,3-butadiene is genotoxic in vitro and 9-fluorenone is cytotoxic, generating reactive oxygen species under light exposure. The substances found in the inks might be partially responsible for adverse skin reactions to tattoos.

Angiotensin II receptor blocker–induced angioedema in the oral floor and epiglottis

We report the rare case of angioedema (also known as Quincke edema), which was induced by valsartan, an angiotensin II receptor blocker (ARB). ARBs are a new class of antihypertensive agent that is developed to exclude the adverse effects of angiotensin-converting enzyme inhibitors. In theory, ARBs do not contribute to the occurrence of angioedema because they do not increase the serum level of bradykinin, the responsible substance for angioedema. However, some reports of ARB-induced angioedema have recently been published. In this study, we present the forth case and the first Asian case of angioedema due to valsartan, which is one of the ARBs. Otolaryngologist should be wary of the prescribing ARB and discontinue ARBs treatment soon, if angioedema is recognized.

Cyclooxygenase inhibition attenuates sympathetic responses to muscle stretch in humans

Passive muscle stretch performed during a period of post-exercise muscle ischemia (PEMI) increases muscle sympathetic nerve activity (MSNA), and this suggests that the muscle metabolites may sensitize mechanoreceptors in healthy humans. However, the responsible substance(s) has not been studied thoroughly in humans. Human and animal studies suggest that cyclooxygenase products sensitize muscle mechanoreceptors. Thus we hypothesized that local cyclooxygenase inhibition in exercising muscles could attenuate MSNA responses to passive muscle stretch during PEMI. Blood pressure (Finapres), heart rate, and MSNA (microneurography) responses to passive muscle stretch were assessed in 13 young healthy subjects during PEMI before and after cyclooxygenase inhibition, which was accomplished by a local infusion of 6 mg ketorolac tromethamine in saline via Bier block. In the second experiment, the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased prostaglandin synthesis to approximately 34% of the baseline. Before ketorolac Bier block, passive muscle stretch evoked significant increases in MSNA (P < 0.005) and mean arterial blood pressure (P < 0.02). After ketorolac Bier block, passive muscle stretch did not evoke significant responses in MSNA (P = 0.11) or mean arterial blood pressure (P = 0.83). Saline Bier block had no effect on the MSNA or blood pressure response to ischemic stretch. These observations indicate that cyclooxygenase inhibition attenuates MSNA responses seen during PEMI and suggest that cyclooxygenase products sensitize the muscle mechanoreceptors.

Expression of MIS in the testis is downregulated by tumor necrosis factor alpha through the negative regulation of SF-1 transactivation by NF-kappa B.

The expression of Mullerian inhibiting substance (MIS), a key molecule in sex differentiation and reproduction, is tightly regulated. It has been suggested that meiotic germ cells repress MIS expression in testicular Sertoli cells, although the substance responsible for this cell-cell communication remains unknown. Here, we present the cytokine tumor necrosis factor alpha (TNF-alpha) as a strong candidate for such a substance and its downstream molecular events. TNF-alpha inhibited MIS expression in testis organ cultures, and TNF-alpha(-/-) testes showed high and prolonged MIS expression. Furthermore, in transient-transfection assays TNF-alpha suppressed the MIS promoter that was activated by steroidogenic factor 1 (SF-1), one of the major transcription factors that regulate MIS expression. The modulation of SF-1 transactivation by TNF-alpha is through the activation of NF-kappa B, which subsequently interacts with SF-1 and represses its transactivation. The physical association of NF-kappa B with SF-1 was shown by yeast two-hybrid protein interaction, glutathione S-transferase pull-down, and coimmunoprecipitation (ChIP) analyses. ChIP assays also revealed that endogenous NF-kappa B, as well as SF-1, is recruited to the MIS promoter upon TNF-alpha signaling. SF-1-bound NF-kappa B subsequently recruits histone deacetylases to inhibit the SF-1-activated gene expression. These results may identify, for the first time, the responsible substance and its action mechanism underlying the repression of MIS expression by meiotic germ cells in the testis.

Pyrrole: From Dippel to Du Pont

The preacher-alchemist Johann Konrad Dippel made an oil by the destructive distillation of bones about 1700. He proclaimed it to be a universal remedy. Much later Ferdinand Runge detected the presence of pyrrole, but not in bone oil. He observed the red color of the pine splint wet with hydrochloric acid in the vapor of coal tar distillate, and called the responsible substance pyrrole. He suggested that it might also occur in bone oil. In the mid-1880's, Thomas Anderson finally isolated pyrrole by repeated distillation of about 250 gallons of ivory oil. About the middle of this century Du Pont began to make it synthetically.

Wheat Flour Compound that Produces Sticky Dough: Isolation and Identification

ABSTRACTSome wheats have a 1B/1R translocation and may produce flours that give sticky doughs, even with optimum mixing time and water absorption. Studies showed that the water‐soluble fraction caused sticky dough. Dialysis experiments indicated that the responsible substance had low molecular weight. Ionic exchange showed it to be either neutral or negatively charged. Gel filtration chromatography indicated it was both carbohydrate and UV‐absorbing. Saponification caused it to lose ability to cause sticky dough. The UV‐absorbing material and the carbohydrate had to be linked for the compound to be active. HPLC mass spectrometry indicated the UV‐absorbing fraction was ferulic acid and the carbohydrate was a hexose.

Organic substance metabolism during seed germination ofPinus bungeana

The metabolism of fats, proteins and carbohydrates and change of enzyme of seeds ofpinus bungeana during the germination were conducted by the methods of gas-liquid chromatography, flow injection, colorimetric analysis of spectrophotometer, to provide theoretical basis for seeds dormancy, germination and storage of seeds of forest tree. The results indicate that (1) carbohydrates were first utilized during germination of seed ofpinus bungeana; (2) stored substances in seeds began to decompose quickly after radicale broke through seed coats; (3) the activity of enzymes in the seeds does not always coincides with the increase or decrease in quantity of its responsible substance during germination of the seed. Changes in stored substance relate to metabalism of other metabolism of other materials and the use of hydrolysates.

Drug protein binding in chronic renal failure: Evaluation of nine drugs

In this study, changes of protein binding of nine drugs were evaluated. In addition, theophylline and phenytoin, the two drugs with the most substantial and progressive decrease in protein binding, were further studied by high performance liquid chromatography (HPLC)-fractions of ultrafiltrate of normal and uremic serum, in an attempt to identify substances causing drug protein binding inhibition. There was a marked decline of the protein binding of theophylline, phenytoin and methotrexate (dialyzed patients vs. normals: -20.1, -16.0 and -15.1%, respectively). There was a rise in the protein binding of propranolol, cimetidine and clonidine. The changes observed for diazepam, prazosin and imipramine were less marked. For phenytoin, theophylline, methotrexate and diazepam, protein binding was inversely correlated to the serum creatinine (r = 0.87, 0.80, 0.79 and 0.67, P less than 0.001), and a less pronounced but still significant positive correlation was found for clonidine (r = 0.46, P less than 0.01). Ultrafiltrate, obtained during a hemofiltration session, inhibited protein binding of theophylline and phenytoin in a dose dependent way. After separation of this ultrafiltrate by HPLC, it appeared that for both theophylline and phenytoin at least a part of this inhibitory activity corresponded to the elution zone of hippuric acid. For theophylline two other inhibitory zones were further recognized: one corresponding to the elution zone of NaCl and one in which the responsible substance remained unidentified. Hippuric acid in solution inhibited protein binding of theophylline and phenytoin in a dose dependent way. In conclusion, protein binding of several drugs currently used in renal failure is affected in parallel with renal function, which might affect the therapeutic effectiveness of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyponatremic seizures as a presenting symptom of child abuse

Poisoning is an uncommon manifestation of child abuse. The intentional administration of water to a child as a form of punishment has rarely been reported as the responsible substance among children who have been poisoned. We describe a case of a 5-year-old girl presenting with severe hyponatremia due to acute water intoxication. The patient was brought to the emergency room in status epilepticus. A history was obtained from the child's mother stating that the patient had been playing outside when she collapsed. She had had no known prior illnesses. Laboratory evaluation included a hemoglobin of 10.1 mg%, glucose of 60 mg%, serum sodium of 107 mEq/l, potassium of 3.2 mEq/l and chloride of 71 mEq/l. A CAT scan obtained approximately 1 h after admission revealed generalized cerebral edema. Careful examination of the skin revealed multiple linear ecchymosis of varying ages on the back and thighs and a hand print on the right flank. In addition, the child demonstrated severe failure to thrive with height, weight and bone age compatible with a 2.5-year-old girl. Appropriate therapy for severe hyponatremia was successfully instituted. For the next 12 h she was deeply somnolent, but the following morning was alert and conversant. She stated that she “would be good if she didn't have to drink any more water”. The child's mother subsequently admitted that she frequently used water ingestion as a form of punishment. The child stabilized metabolically and demonstrated rapid in-hospital weight gain. She was placed in foster care at discharge and has had no further hyponatremia or seizures. In our patient, hyponatremic seizures represented a manifestation of chronic and systematic abuse due to intentional water intoxication. Primary caregivers and pathologists should be aware that hyponatremia without underlying disease may be evidence of child abuse.

Characterization and partial purification of keratinocyte growth factor from the hypothalamus.

An extract of bovine hypothalamus is known to be mitogenic for human keratinocytes in vitro. In order to identify the responsible substance(s), biochemical characterization and subsequent bioassay of the extract in a serum-free culture system were performed. The keratinocyte growth-promoting activity of the hypothalamic extract was unaffected by heating (100 degrees C, 10 min); acidification to pH 3.3; or by exposure to lipase, RNAase, or proteolytic enzymes; but was abolished by alkalinization to pH 11. An approximate molecular weight of 1,700 daltons was determined by elution on a calibrated Sephadex G-25 column, and an approximate pl of 3.5 was determined by isoelectric focusing. Optimal concentrations of the crude extract (150-300 micrograms/ml) increased keratinocyte growth approximately 50-fold compared to control cultures lacking the extract. Partial purification resulted in a preparation biologically active at 30 ng/ml protein equivalent and was consistent with the presence of a single mitogen which we have termed keratinocyte growth factor (KGF). Mitogenic activity for human melanocytes, dermal fibroblasts, and endothelial cells, present in the crude hypothalamic extract, was lacking in heat-treated preparations that contained KGF. Optimal concentrations of purified epidermal growth factor and ethanolamine, the only remotely similar substances previously reported to augment keratinocyte growth in vitro, could not substitute for KGF in the serum-free culture system. Keratinocyte growth-promoting activity comparable to that observed in bovine hypothalamic extracts was present in human hypothalamic extracts prepared in the same manner.

Substance Abuse Education in the U. S. Air Force

The USAF Substance Abuse Seminar represents a new phase of preventative drug and alcohol abuse education, which has been implemented Air Force wide. The four hour seminar is presented to the general Air Force population on an event oriented basis. It is designed specifically to raise the level of substance abuse awareness among Air Force members and emphasize substance abuse information in relation to the individual's role and responsibilities within the Air Force. The seminar includes: (1) Air Force Drug/Alcohol Abuse Control policies, relating to substance use by Air Force members; (2) local conditions, regarding substance abuse; (3) socio-pharmacology, concerning the status of substances relative to their effects; and (4) personal responsibility in the use of substances, reflecting the concept of responsible substance use. Further information concerning the objectives and implementation of the seminar program is presented.

Hyperpigmentation Due Solely to Increased Plasma ß-Melanotropin

In 1958, Nelson and others¹described a patient with dark skin, enlargement of the sella turcica, and an elevated level of plasma corticotropin (ACTH), all appearing after adrenalectomy for Cushing's disease. At the time it was not clear whether ACTH or melanocyte-stimulating hormone (MSH) caused the hyperpigmentation. Since such patients have increased levels of MSH as well as of ACTH,²it has been difficult to state conclusively that one or the other hormone is the responsible substance. We report here a patient with hyperpigmentation after total bilateral adrenalectomy for Cushing's disease, who lacked two of the findings usually found in Nelson's syndrome, namely, an enlarged sella turcica and an elevated plasma level of ACTH, but who did have a high level of β-MSH in his plasma. <h3>Patient Summary</h3> In 1959, a 41-year-old man had typical clinical signs and symptoms of Cushing's syndrome with the level of urinary 17-hydroxycorticosteroids