Analysis of the prevalence of thrombocytopenia in a multidisciplinary hospital, where it is treated about 25,000 patients a year, shows that from 1.15% to 1.45% of patients have threat reduction platelets less than 100x109/l. 40,2% of them (on average, 127 people per year) receive heparin and can potentially be seen as patients that are suspected to heparin-induced thrombocytopenia (HIT). Timely identification of such patients, the use of two rules – 4T and «100–5—100» allows you not to miss the patient with the development of HIT, time to switch to alternative anticoagulants and, if necessary, to stop the flushing of venous catheters with heparin solution. This tactic allows to reduce the number of patients, receiving heparin and thrombocytopenia below 100 х 109/l, almost 3 times as took place among hospitalized and patients in intensive care units in 3 years of using the mentioned tactics.

According to the World Health Organization estimates, non-alcoholic fatty liver disease (NAFLD) will be ranked number one in the liver diseases pattern by 2020. Liver transplantation in patients with cirrhosis as the outcome of NAFLD currently ranks next to the viral liver cirrhosis. According to current concepts, NAFLD is a liver disease defined as fatty dystrophy, fatty degeneration with inflammation and possible outcome in cirrhosis. The causal relationship between NAFLD and diabetes mellitus is the subject of numerous discussions. Insulin resistance is the binding pathogenetic link between one and the other disease. First of all, insulin resistance is carried out at the level of hepatocyte. Until now, there is no standard therapy for NAFLD. Correction of body weight, changes in food addiction, physical activity is the most effective measures to prevent the development of NAFLD and diabetes mellitus. None of the drugs used for the treatment of NAFLD has evidence base for the effect on the histological pattern of NAFLD.

The prospective randomized trial included 167 patients with functional class II-III of  chronic heart failure (CHF) and a preserved left ventricular ejection fraction (LVEF) affected by hypertensive disease of stage III. In addition to antihypertensive therapy with perindopril and verapamil SR (n = 85) or amlodipine (n = 82), atorvastatin was prescribed, which was regularly taken by 50.6% and 48.8% of patients, respectively. After 12 months, patients in each treatment arm showed improvement in the clinical condition and quality of life, an increase in 6MWD (6-minute walk distance). The patients receiving atorvastatin demonstrated a significant reduction in the N-terminal prohormone of brain natriuretic peptide (NT-proBNP or BNPT) level, and a tendency to improve a diastolic LV function. Adding atorvastatin to the therapy of CHF with preserved LVEF may reasonably improve the prognosis of patients.

The incidence of atherosclerosis in the arteries of the lower extremities is increasing all over the world, and studies conducted in several countries have shown that increased incidence of chronic obliterating diseases of lower extremity arteries is associated with other cardiovascular events, and with poor prognosis. The development of an algorithm for an integrated approach to treatment that will make it possible to personalize the drug therapy in this group of patients was one of the ways to improve the long-term results of reconstructive interventions on the arteries of the lower extremities. The study included 105 patients of both sexes (mean age 68 ± 1) who underwent reconstructive surgery on the arteries due to obliterating atherosclerosis of the lower extremities followed-up in the City Diagnostic Center No. 1 in St. Petersburg from 2008 until now. Before seeking treatment, all patients received acetylsalicylic acid (ASA) 100 mg per day as antiplatelet therapy.  The antiplatelet therapy was adjusted on the basis of clinical data, taking into account the laboratory and molecular genetic test results. The functional activity of platelets was monitored according to the ADP- and collagen-induced impedance aggregation indices.  Identification of genetic peculiarities of the drug metabolism and the factors that influence platelet aggregation and the simultaneous laboratory evaluation of the functional activity of platelets made it possible to achieve the stably low residual reactivity of platelets in all patients included in the study by assigning an individual regimen (ASA monotherapy, clopidogrel monotherapy, DAT) and doses (ASA 100 mg or 150 mg per day) of antiplatelet agents.

The study included 75 women with arterial hypertension, aged 48-51 years (Me 50,0 years [25%; 75%: 48,0; 52,0 years]), who according to the clinical laboratory and instrumental examination was diagnosed essential hypertension (EH) I–II stage of 1–2 degrees. The duration of arterial hypertension did not exceed 5 years (Me 1 year [25%; 75%: 1; 3 years]) and all women had moderate risk of cardiovascular complications on the SCORE scale. All patients were in the perimenopausal period, confirmed by laboratory of hormonal status. After 14 weeks of monotherapy losartan or ramipril or combination with one of RAAS blockers and bisoprolol with low-dose hydrochlorothiazide was achieved target blood pressure and improvement of endothelial and kidney function, which was manifested by decrease in the level of albuminuria and ADMA concentration, significantly exceeding the reference values in the initial state. More pronounced organoprotective effect was in the group of women, receiving combined antihypertensive therapy.

Objective: evaluate antihypertensive and vasoprotective effects of fosinopril in patients with arterial hypertension with a high and very high risk of cardiovascular complications. Material and methods. The open study included 26 Grade 2 hypertensive patients with high and very high cardiovascular risk. Among them were 13 (50%) women, 13 (50%) men, the average age of which was 58.1 ± 10.3 years. Initially, all patients received hydrochlorothiazide diuretic therapy at a dose of 12.5 mg per day and various ACE inhibitors, but target blood pressure levels were not achieved. Fosinopril, an angiotensin converting enzyme (ACE) inhibitor (Monopril, VALEANT LLC, Russia), was administered to correct blood pressure for all patients instead of ACE inhibitors which they received earlier. The patients underwent a complete clinical and instrumental examination. The emphasis was placed on the study of the endothelial function by instrumental and laboratory methods. A test with endothelium-dependent vasodilatation (EDVD) was performed using method D. Celermajer; the total concentration of nitrate- and nitrite ions (NO2, NO3) in the blood serum was determined by the colorimetric method. The results of the examination were compared before administration of the drug and after 4 weeks of treatment. Results. 22 patients (85%) could achieve the target level of blood pressure (less than 140/90 mm Hg) after 8 weeks of fosinopril treatment. Daily monitoring of blood pressure showed a significant decrease in the variability of both systolic (SBP) and diastolic blood pressure (DBP). Initially, the dilatation reaction of the brachial artery was reduced in all patients and averaged to 6.8 ± 1.9%. The level of NO2 was 18.1 ± 0.9 μmol/l, NO3 – 28.8 ± 0.3 μmol/l. After 4 weeks of treatment, the EDVD increased to 7.5 ± 2.9%. The level of NO2 was 19.3 ± 0.4 μmol/l, NO3 – 38.75 ± 0.54 μmol/l. Conclusion. Fosinopril, an ACE inhibitor, had a pronounced antihypertensive effect, and improved endothelial function in patients with hypertension with a high and very high risk of cardiovascular complications after 4 weeks of treatment.

Various joint pain syndromes are one of the frequent causes of treatment of patients not only to a traumatologist, but also to a neurologist. The urgency of the problem of pain syndromes in the shoulder is discussed in the article. Detailed anatomical and physiological features of the shoulder joint and periarticular soft tissues are highlighted. The characteristic of the most common etiological and pathogenetic mechanisms of the development of pain syndrome in the region of the shoulder joint is given. Part of the article is devoted to the clinical features and diagnosis of pain in the shoulder region, depending on the etiological factor of pain. In the article discussed modern pharmacological and non-pharmacological methods of treatment of shoulder pain. A clinical example of differential diagnosis of pain and treatment with drug Nimesil is considered.

Pain is one of the most common symptoms in modern clinical practice and one of the most common reasons why patients seek medical care at an outpatient clinic. Traditionally, nonsteroidal anti-inflammatory drugs (NSAIDs) are the leading means of protecting peripheral pain receptors. However, with the intake of NSAIDs, a whole range of different complications is associated. Comorbidity and drug safety are closely related to the use of NSAIDs. In the presented review, domestic and foreign studies of dexketoprofen for the treatment of pain syndrome in the outpatient and polyclinic stage were analyzed. The emergence of the domestic brand-generic dexketoprofen, the drug Flamadex®, in the Russian pharmaceutical market increases the availability of effective and safe therapy of pain syndrome in patients with comorbid pathology at the outpatient and polyclinic stage.

The abdominal pain is diverse on the parentage (visceral, reflected, central-mediated, senesthopathias, neuropathic). The neuropathic abdominal pain is a little familiar to therapists. It has the clinical features: an allodynia (hyperalgesia), a hygromania, a combination to vegetative dysfunction. On a forward abdominal wall painful trigger points and a positive Carnett’s symptom are defined. Elimination of a neuropathic abdominal pain is reached by means of course application of a combination of medical products (local anaesthetics, non-opioid analgetics, anticonvulsants, antidepressants), and at their insufficient efficiency the surgical intervention (excision of terminal departments of intercostal nerves in the field of a direct muscle of a stomach) is shown. Efficiency of similar complex treatment reaches 73%.

Rhinorrhea is a term for abundant mucous (watery) discharge from the nasal cavity, which originated from the Greek word «rhoia» (flow, discharge). Rhinorrhea is usually a symptom of acute diseases. However, less pronounced manifestations can be a sign of various chronic diseases not only of the nasal cavity, but of other organs and systems. In order to identify the causes for rhinorrhea, you may need to take an additional examination and a detailed history of occupational diseases, medications taken, etc. The patients should receive symptomatic treatment while awaiting the laboratory test results and identification of the causes for the disease.

The article is devoted to the peculiarities of managing patients with acute bronchitis. It provides data on the etiological causes of development and the main clinical manifestations of some individual disease courses. The discussion of issue of prescribing antibacterial drugs for the treatment of this disease includes feasibility, basic indications and contraindications, risk markers for the development of complications. The emphasis is made on the practical use of azithromycin macrolide antibiotic (Azitral 500 mg). Clinical cases of real patients are provided.

The article presents epidemiology, pathogenesis and classification of allergic rhinitis. The highlights of the article include nonpharmacological and pharmacological methods of treatment of this disease, and the efficacy of different groups of drugs for relief and management of allergic rhinitis symptoms.

Influenza is one of the most common diseases with a high risk of complications. Modification of influenza viruses causes epidemics and annual vaccination of the population. In the coming year, a new subtype of Michigan influenza related to the swine H1N1-influenza with a potentially severe course is expected. Antiviral drugs are essential components of a comprehensive pandemic response. Oseltamivir, zanamivir, peramivir are the new generation neuraminidase inhibitors which are considered to be the most effective drugs. A new domestic antiviral drug Nomides (oseltamivir phosphate) is the recommended drug for the treatment of influenza. It is safe and affordable for the majority of the population. Active immunization, i.e. vaccination, is the most effective method of preventing influenza.

The article presents the results of eradication treatment of 30 patients with duodenal ulcer associated with H. pylori (HP) infection. A new combination of drugs was used: Controloc at a dose of 80 mg/day, Combiflox (combination of ornidazole and ofloxacin) for 10 days. 80% of patients achieved eradication. 3% of patients reported side effects, which were neither severe, nor required a change in the treatment pattern.

The article presents data on functional constipation (FC): the definition (including the one of the last consensus – Rome IV), epidemiology, diagnostics, general approaches to the treatment and the results of using the stimulant drug Slabilen manufactured by the domestic firm Veropharm. 30 patients received the drug, and the positive effect accounted for 90%. The advantage of the drug is a double mechanism action: stimulating and osmotic. No pathological effects have been detected.

Efforts are under way to find optimal therapy for Helicobacter pylori (H. Pylori)-associated gastrointestinal diseases. Among such diseases are gastric and duodenal ulcers, gastritis (atrophic gastritis), functional dyspepsia, gastropathies induced by non-steroidal antiulcer drugs (NSAIDs). Various regimens for eradication of Helicobacter pylori infection are typically chosen on the basis of administration of proton pump inhibitors (PPI), antibiotics, metronidazole in different doses and combinations, as well as bismuth salts products, mainly bismuth tripotassium dicitrate (BTD). The article explores the possibility for participation in the eradication therapy regimens with a domestic BTD-based drug – Novobismol®. The studies showed that Novobismol® was successfully used in anti-Helicobacter therapy in patients with peptic ulcer, chronic gastritis, and in patients with functional dyspepsia. It can be concluded that the BTD-based drug Novobismol® is effective and safe, and its use extends the possibilities of treating H. Pylori-associated diseases.

Ulcerative colitis (UC) is a chronic disease characterized by immune diffuse inflammation of the mucosa of the colon with mandatory involvement in the inflammatory process of the rectum. The choice of conservative or surgical treatment depends upon the severity of the attack, extent of lesions of the colon, presence of extraintestinal manifestations, duration of disease, efficacy and safety of past therapy and the risk of complications UC. In Russia and abroad for the treatment and prevention of relapses of UC are widely used mesalazine having minimum side effects. Our study shows high adherence of patients to receive drugs 5-ASA and the positive impact of the use of oral medications 5-ASA Salofalk and Asacol for the maintenance of remission in patients UC moderate severity in clinical practice. This study also showed the importance of long-term use (at least 12 months) drugs 5-ASA to maintain remission and reduce the risk of disease recurrence.

A patient with Child-Pugh B cirrhosis as the outcome of chronic hepatitis C (HCV), genotype 1b was treated with ombitasvir/ paritaprevir/ritonavir/dasabuvir (Viekira Pak) and ribavirin (Ribavirin-SZ) for 12 weeks with achievement of sustained virological response. 48 weeks after the end of the antiviral treatment the patient developed acute viral hepatitis with high level of liver aminotransferases caused by the hepatitis C virus genotype 3a. On day 18 of hospitalization antiviral therapy with sofosbuvir 400 mg per day and daclatasvir 60 mg per day for 12 weeks was administered. Drug tolerance was good, biochemical and sustained virological response was achieved.

The article describes various etiological forms of esophagitis, such as reflux-induced, infectious: viral, fungal, bacterial, allergic, dysmetabolic, the one caused by systemic diseases, radiation, medicinal, eosinophilic. The main principles of management of these forms are provided. The paper defines a role of proton pump inhibitors in the treatment of various forms of esophagitis. Rabeprazole is the most effective agent of the group for the treatment of esophagitis. The results of clinical observation of daily pH-metry with the use of rabeprazole are presented.

The article analyzes the results of local treatment of 63 patients with osteoarthrosis of the knee-joints II – III stages. It is shown, that the use of therapy with APRP and hyaluronic acid is clinically more effective than the traditional method of treatment in patients with gonarthrosis without synovitis.

Osteoarthritis (syn: arthrosis, osteoarthritis, osteoarthritic disease, deforming osteoarthritis, degenerative arthropathy, degenerative-dystrophic joint disease, Kellgren’s disease, etc.) is a heterogeneous group of joint diseases of various etiology with similar biological, and clinical and morphological manifestations and outcome, which gave occasion to determine its phenotypes at the current stage of studying this pathology.

In the current context, immunosuppressive therapy of systemic rheumatic diseases (RD) is becoming more widespread. At the same time, the active use of immunosuppressors including genetically engineered biological preparations is accompanied by an increase in opportunistic infections. The latter include pneumocystic pneumonia (PPn), which is a serious complication with significant mortality in patients with RD. However, given the heterogeneous data on the risks of specific RH and some or other immunosuppressive therapy, the development of a evidence-based comprehensive guide on the prevention of PPn in rheumatology is currently not possible. Specific guidelines for practical physicians can serve as algorithms of PPn prevention published by different authors, which are sure to be further followed-up (or processed) as new data are accumulated within the framework of the problem under consideration.

In the current context, immunosuppressive therapy of systemic rheumatic diseases (RD) is becoming more widespread. At the same time, the active use of immunosuppressors including genetically engineered biological preparations is accompanied by an increase in opportunistic infections. The latter include pneumocystic pneumonia (PPn), which is a serious complication with significant mortality in patients with RD. However, given the heterogeneous data on the risks of specific RH and some or other immunosuppressive therapy, the development of a evidence-based comprehensive guide on the prevention of PPn in rheumatology is currently not possible. Specific guidelines for practical physicians can serve as algorithms of PPn prevention published by different authors, which are sure to be further followed-up (or processed) as new data are accumulated within the framework of the problem under consideration.

A review of the literature is devoted to the issue of secondary hyperparathyroidism (SHPT) with underlying chronic renal failure. Initial manifestations of the disease can be observed even with a minimal decrease in the rate of glomerular filtration and are pathophysiologically associated with violations of normal metabolism of vitamin D with its conversion into D-hormone. SHPT pathogenesis is based on the D-hormone deprivation and triggering of pathophysiology mechanisms of bone remodelling, increased FRP-23, PTH, changes in the serum levels of calcium and phosphorus, which may further lead to significant changes in the bone tissue structure and cardiovascular complications. Active metabolites of vitamin D and vitamin D analogues (Paricalcitol) were developed for the replacement of active forms of vitamin D in conditions of D-hormone deficiency. Due to its chemical structure and pharmacokinetics, Paricalcitol is able to block the synthesis of parathyroid hormone to a greater extent and increase the absorption of calcium and phosphorus in the intestine to a lesser extent, which gives it advantages over pre-existing active metabolites

Background: Obesity is considered to be the most wide-spared disease all over the world [1]. Having a hormonal activity, adipose tissue takes part in coordinating of metabolic processes. Taking into consideration the excess accumulation of the adipose tissue, the proceeding of metabolic process gets abidingly broken [2]. Aims: The aim of this thesis is to analyze a hormone metabolism of the hormones of adipose tissue among the patients who has obesity. Materials and methods: 30 patients with obesity without any accompanying disease were examined. This examination was done to determine the level of adipokines (leptin, adiponectin, visfatin), insulin with index calculus of insulin resistance, blood lipids. Results: The analysis showed the fact that patients with obesity have a higher level of insulin, leptin in comparison to the control group. However, the level of adiponectin among people from the control group increased the same level of patients with obesity. The essential differences in the level of visfatin has not been discovered. Hyperinsulinemia and Dyslipidemia (increased cholesterol low density lipoprotein (TC-LDL), triglycerides (TG), reduction of cholesterol of high density lipoproteins (HDL – C)) are observed alongside the increase of leptin level among the patients with obesity. Conclusion: Multidirectional changes of hormones of adipose tissue are established among the patients with obesity without somatic pathology in comparison with the ones without obesity and overweight. The determined dynamics of adipokines contributes changes of functioning of physiological systems of out organism and demands the research of more informative and essential methods of correction.

Insulin glargine, synthesized using recombinant DNA technology in a concentration of 100 U/ml, was the first once-daily longacting insulin analogue introduced into clinical practice in 2000. Glargin has a well-established record of efficacy and safety and is the most widely used insulin worldwide. In February 2015, the drug lost its US patent protection, which opened the door for biosimilar competitors.

Skin lesions, increased transepidermal water loss, changes in pH in patients with allergodermathosis lead to a decrease in the protective mechanisms of the skin that makes individuals more susceptible to infections. The development of complications predefined the interest in improving topical therapy. The article presents a brief review of the literature data on high therapeutic activity and good tolerability of the topical drug Triderm. When compared with the original drug, the generics revealed differences in the structural and mechanical properties, which affects bioavailability. A comparison of therapeutic efficacy and tolerability has shown that Triderm is more effective, and comparable to Akriderm GK in terms of tolerability.

The review is devoted to the pathogenetic substantiation of the use of the activated zinc pyrithione agent in atopic dermatitis. The main mechanisms of formation of the pathological process in atopic dermatitis are explained in more details: hereditary predisposition, violations of the barrier function of the skin and immunological dysfunction leading to the development and persistence of chronic inflammation. The role of zinc ions in the pathogenesis of atopic dermatitis is discussed. The article presents the detailed analysis of the main clinical studies of the activated zinc pyrithione agent in atopic dermatitis, its positive effect on such symptoms as itching, skin manifestations, skin microbioma and severity of the disease course.

Idiopathic infertility (II) accounts for up to 30% of male infertility. Antioxidants were empirically used in the treatment of II based on their ability to improve reproductive function suppressed by oxidative stress (OS), which was often found in these patients. The review article was aimed to report the validity of available data confirming the use of antioxidants. Antioxidants such as glutathione, vitamins E and C, carnitines, coenzyme Q10, N-acetylcysteine, selenium, zinc, folic acid and lycopene have been shown to reduce sperm damage caused by OS. Although rigorous scientific evidence in the form of double-blind, placebo-controlled clinical trial is limited, recent systematic reviews and meta-analyses showed a positive effect of antioxidants on sperm parameters and fertility rates. There is, however, a need for further investigation with randomised controlled studies to confirm the efficacy and safety of antioxidant therapy in the medical treatment of idiopathic male infertility as well as the need to determine the effective dose of each compound to improve semen parameters, fertilisation rates and healthy pregnancy outcomes.

Abnormal uterine bleeding (AMC) is a common pathology in women of childbearing age. The review gives the current classification and terminology of AMC, the main causes and mechanisms involved in bleeding. Hormonal contraception has been successfully used to control the menstrual cycle in sexually active women. The article is intended to provide research data on the use of hormonal contraceptives, assess the use of hormonal contraceptives in AMC therapy caused by various diseases, and describe the characteristics of evidence-based hormonal contraceptives to be used by women with AMC of various origins who need protection against unwanted pregnancy.

One of the most significant problems of modern health care is the increasing incidence of malignant neoplasms of different localization, in particular cervical cancer. Malignant tumor of this localization develops on the basis of a cascade of precancerous changes in the cervix epithelium. Cervical dysplasia is a multifactorial disease, but the inflammation factor, especially associated with the presence of a specific pathogenic agent plays a major role in the unrelenting growth of cancer cells. When planning combination therapy in the settings of the inflammatory process, not only etiotropic therapy aimed at eliminating the pathogen, but also the correction of the immune status is of great importance, which makes it possible to achieve a stable therapeutic effect, including accelerating the regress of dysplastic changes in the cervical epithelium. Our examination and treatment of 47 patients with cervical dysplasia associated with colpitis of specific etiology (T. vaginalis, C. trachromatis) proved the advantage of combination therapy with Galavit as compared with the standard course of antibacterial and anti-inflammatory therapy.

Anemia is common in women during pregnancy and in the postpartum period. This disorder is caused by the physiologically increasing needs of the fetus and often initially reduced iron stores in the mother’s body. Iron deficiency can underlie a number of complications of the gestation period for both the woman and the newborn at a later time. The fastest, most effective and safe management of iron deficiency anemia, especially in its severe forms, allows avoiding complications and improving pregnancy outcomes. Administration of iron supplements is the main method of management of iron deficiency anemia. However, oral forms do not allow achieving the effect in all cases, taking into account the peculiarities of iron absorption from the GI tract. Ferric carboxymaltose is an intravenous drug that has good tolerability and, what is most importantly, effectively and quickly replenishes iron deficiency in pregnant women starting from the second trimester and in the postpartum period.

Definition of the most relevant ways of magnesium deficiency correction and prevention of magnesium-deficiency states complications is an important task. Application of peroral magnesium preparations corrects magnesium deficiency in the pregnant, reduces probability of miscarriage and eclampsy, development of gestational diabetes and obesity

The work presents a short list of methods of rehabilitation and expert examination when referring patients, who have suffered a craniocerebral trauma, to the medical and social assessment. The article emphasizes the urgency of an integrated approach to diagnosis and development of rehabilitation measures, the individual nature of rehabilitation measures was noted. The advantage of young people among other patients who have suffered a craniocerebral trauma is stressed, which is of great importance for the restoration of their social and professional status.

The article is devoted to the study and analysis of the pharmacotherapeutic competence of the graduates of the medical university on the threshold of the independent medical activity in the primary link of public health. 169 students of the 6th year of the Medical Department of Yevdokimov MGMSU responded in writing to 8 tasks which proposed to name the optimal medicinal products (MP) in a number of standard situations of outpatient practice. The mean median of the selection evaluation was 11 points out of 16 impliable meanings. Each respondent indicated his average academic performance and assessed his/her own confidence in reasonable command of pharmacotherapy – the mean median for these indicators was 3 out of 5 and 6 out of 10 points, respectively. All 3 studied parameters showed a very weak positive relationship between themselves in ρ range from 0.19 to 0.24 for p <0.05. In the separate analysis of these indicators in the subgroups of students with high and average academic performance, no relationship between performance, assessment of drug choice and self-assessment of pharmacotherapeutic competence has been identified. The average assessment of the choice of drugs between these subgroups did not differ either. The data given indicate that the best average academic performance does not guarantee higher competence of respondents in the choice of medicines. The authors recommend purposeful pharmacotherapeutic preparation of students on the graduate course, taking into account the specificity of the forthcoming medical activity.

The introduction of advanced radio technologies into practical healthcare provides high-tech, qualified and reliable diagnostics. Radiation methods of visualizing the activity of organs and systems in real time are the basis of personified therapy and prevention of various pathological conditions. The evolution of telecommunication networks and mobile communication technologies has led to appearance a new direction in healthcare – distance medicine. Using of radio frequency identification systems, wireless medical telemetry, telemedicine not only improves the quality of life of patients, but also ensures the availability of medical care in any place and at any time.