Erectile dysfunction and diabetes mellitus: mechanistic considerations from studies in experimental models

Diabetes is a major risk factor for erectile dysfunction. The condition degrades both neural and vascular endothelium penile control systems. Experimental and epidemiological evidence suggest that both hyperglycemia and dyslipidemia contribute to the etiology. These are the driving forces for elevated oxidative stress and the formation of advanced glycation and lipoxygenation end products, the major target being the nitric oxide systems of nerve and endothelium. This causes reversible functional loss followed by less reversible degenerative changes. These mechanisms have direct effects, such as the nitric oxide quenching, but perhaps more importantly, indirect effects on the regulation of nitric oxide synthase expression and activity, which can involve recruitment of proinflammatory cell signaling pathways. The latter include protein kinase C, mitogen-activated kinases, and the nuclear factor kappa B cascade. Diabetes also changes the trophic influences on nerve and endothelium. Together, these form potential therapeutic targets against diabetic erectile function, and indeed vascular disease in general.     

Treatment selection considerations for the hypertensive diabetic patient

Hypertension occurs with twice the frequency in the diabetic population as compared with the general nondiabetic population. Treatment of hypertension in diabetics can be complicated by diabetic complications and the potential for adverse effects from selected antihypertensive drugs. A rational approach to antihypertensive therapy in diabetics with or without concurrent diabetic complications incorporates a "stepped" approach to therapy that includes alternative step 1 agents (eg, angiotensin-converting enzyme inhibitors and calcium channel blockers) rather than traditional agents (eg, diuretics and beta-blockers). Evolving evidence with angiotensin-converting enzyme inhibitors reveals that they do not exacerbate complications of diabetes mellitus and also may arrest or slow the progression of diabetic nephropathy. Treatment algorithms for a stepped approach to the management of the hypertensive diabetic patient are proposed.     

Antibiotic selection for urinary tract infection: New microbiologic considerations

Urinary tract infection (UTI) is an extremely common clinical condition, especially among women, half of whom will have at least one episode of acute cystitis at some point during adult life. An estimated one quarter of these women will have frequent, recurrent UTI. The microbiology of uncomplicated UTI is very predictable, with the vast majority of cases attributed to Escherichia coli. Recent reports from the United States and Europe have shown that resistance among uropathogens to agents that have traditionally been recommended as firstline therapy for uncomplicated UTI is on the rise. Although resistance to fluoroquinolone antibiotics among community-acquired uropathogens remains very low in the United States, fluoroquinolone resistance in community-acquired UTI isolates from other parts of the world has been increasingly described. Very low levels of resistance to nitrofurantoin among uropathogens has revived interest in this agent. The effect of in vitro resistance in uropathogens on the clinical response to treatment of acute cystitis is not well studied. The implications of emerging resistance among the causative agents of this extremely common infection for therapy of UTI are discussed.     

Gut microbiota in various childhood disorders: Implication and indications

Gut microbiota has a significant role in gut development, maturation, and immune system differentiation. It exerts considerable effects on the child's physical and mental development. The gut microbiota composition and structure depend on many host and microbial factors. The host factors include age, genetic pool, general health, dietary factors, medication use, the intestine's pH, peristalsis, and transit time, mucus secretions, mucous immunoglobulin, and tissue oxidation-reduction potentials. The microbial factors include nutrient availability, bacterial cooperation or antagonism, and bacterial adhesion. Each part of the gut has its microbiota due to its specific characteristics. The gut microbiota interacts with different body parts, affecting the pathogenesis of many local and systemic diseases. Dysbiosis is a common finding in many childhood disorders such as autism, failure to thrive, nutritional disorders, coeliac disease, Necrotizing Enterocolitis, helicobacter pylori infection, functional gastrointestinal disorders of childhood, inflammatory bowel diseases, and many other gastrointestinal disorders. Dysbiosis is also observed in allergic conditions like atopic dermatitis, allergic rhinitis, and asthma. Dysbiosis can also impact the development and the progression of immune disorders and cardiac disorders, including heart failure. Probiotic supplements could provide some help in managing these disorders. However, we are still in need of more studies. In this narrative review, we will shed some light on the role of microbiota in the development and management of common childhood disorders.     

Regional anesthesia for thoracic surgery: a narrative review of indications and clinical considerations

Background and ObjectiveSurgical procedures involving incisions of the chest wall regularly pose challenges for intra- and postoperative analgesia. For many decades, opioids have been widely administered to target both, acute and subsequent chronic incisional pain. Opioids are potent and highly addictive drugs that can provide sufficient pain relief, but simultaneously cause unwanted effects ranging from nausea, vomiting and constipation to respiratory depression, sedation and even death. Multimodal analgesia consists of the administration of two or more medications or analgesia techniques that act by different mechanisms for providing analgesia. Thus, multimodal analgesia aims to improve pain relief while reducing opioid requirements and opioid-related side effects. Regional anesthesia techniques are an important component of this approach.MethodsFor this narrative review, authors summarized currently used regional anesthesia techniques and performed an extensive literature search to summarize specific current evidence. For this, related articles from January 1985 to March 2022 were taken from PubMed, Web of Science, Embase and Cochrane Library databases. Terms such as “pectoral nerve blocks”, “serratus plane block”, “erector spinae plane block” belonging to blocks used in thoracic surgery were searched in different combinations.Key Content and FindingsPotential advantages of regional anesthesia as part of multimodal analgesia regiments are reduced surgical stress response, improved analgesia, reduced opioid consumption, reduced risk of postoperative nausea and vomiting, and early mobilization. Potential disadvantages include the possibility of bleeding related to regional anesthesia procedure (particularly epidural hematoma), dural puncture with subsequent dural headache, systemic hypotension, urine retention, allergic reactions, local anesthetic toxicity, injuries to organs including pneumothorax, and a relatively high failure especially with continuous techniques.ConclusionsThis narrative review summarizes regional anesthetic techniques, specific indications, and clinical considerations for patients undergoing thoracic surgery, with evidence from studies performed. However, there is a need for more studies comparing new block methods with standard methods so that clinical applications can increase patient satisfaction.     

Demographic considerations in the selection of antihypertensive therapy

Because of the growing number of antihypertensive agents that are suitable for initial therapy in mild and moderate hypertension, it is important to identify factors that influence the response to various medications. Although individual patient considerations, such as associated illnesses and potential side effects, are of primary importance in choosing therapy, the influence of demographic factors has received increasing attention. The effect of age, race and gender on the response to antihypertensive therapy will be examined. Several studies have indicated that the beta blockers and angiotensin converting enzyme (ACE) inhibitors are more effective in younger than in older patients. Conversely, there is a trend toward greater responses in older subjects to the diuretics and calcium antagonists. In the few studies available that have compared agents in various classes, it appears that diuretics, and probably calcium antagonists, are significantly more effective than beta blockers or ACE inhibitors in patients over 60 years of age. However, the interdrug differences in young patients are probably less important. With regard to race, the relative lack of effect of beta blockers and ACE inhibitors in blacks is well accepted; in comparative studies, diuretics proved significantly better. From the few available studies, it does not appear that the calcium antagonists are more potent in either racial group, but they may be superior to the beta blockers and ACE inhibitors in blacks. Far less information is available concerning differences in antihypertensive responses between men and women. There is some suggestion that women may be less responsive to beta blockers than men.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evolutionary pattern in the OXT-OXTR system in primates: Coevolution and positive selection footprints

Oxytocin is a nonapeptide involved in a wide range of physiologic and behavioral functions. Until recently, it was believed that an unmodified oxytocin sequence was present in all placental mammals. This study analyzed oxytocin (OXT) in 29 primate species and the oxytocin receptor (OXTR) in 21 of these species. We report here three novel OXT forms in the New World monkeys, as well as a more extensive distribution of a previously described variant (Leu8Pro). In structural terms, these OXTs share the same three low-energy conformations in solution during molecular dynamic simulations, with subtle differences in their side chains. A consistent signal of positive selection was detected in the Cebidae family, and OXT position 8 showed a statistically significant (P = 0.013) correlation with litter size. Several OXTR changes were identified, some of them promoting gain or loss of putative phosphorylation sites, with possible consequences for receptor internalization and desensitization. OXTR amino acid sites are under positive selection, and intramolecular and intermolecular coevolutionary processes with OXT were also detected. We suggest that some New World monkey OXT-OXTR forms can be correlated to male parental care through the increase of cross-reactivity with its correlated vasopressin system.Oxytocin has crucial functions related to physiological processes and social behaviors in primates and other placental mammals. A nonapeptide (Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly) (1), oxytocin (OXT-8Leu) is both a neurotransmitter released by neuronal cells in synapses and a hormone, activating receptors distant from the site of its synthesis through the circulatory system (2). In mammals, OXT acts as a hormone in uterine contraction during parturition and in milk ejection while lactating. It is also a key central nervous system neurotransmitter, regulating/modulating complex social and reproductive behaviors (i.e., pair bonding and parental care) (3–7).Until recently, it was believed that the OXT amino acid chain was the same in all placental mammals. However, Lee and colleagues (8) reported a T > C change in four New World monkeys (NWms), Saimiri sciureus, Cebus apella, Callithrix jacchus, and Aotus nancimae, substituting leucine to proline at position 8 (OXT-8Pro). This form was also found in Tupaia belangeri, a tree shrew species of Southeast Asia (8). OXT differs from its paralog vasopressin (AVP; Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly) at positions 3 and 8. Variation at position 8 also identifies nonplacental OXT/AVP-like nonapeptides, such as mesotocin, present in some marsupials (7, 9). These findings dispel the notion of a universal OXT amino acid sequence for placental mammals. They also suggest that residue variability at position 8, in some cases associated with variations at positions 2–5, may be connected with the recognition, binding, and activation of receptors, potentially leading to species-specific functional changes (7, 10).OXT activity depends on adequate interaction with its unique receptor, OXTR, although it can also bind to the vasopressin receptors (AVPR1a, AVPR1b, and AVPR2) with lower affinity (11–13). Similar to other receptors that use G proteins as transducer signals across the cell membranes, OXTR is composed of seven transmembrane (TM1–TM7), four extracellular (N-terminal tail-ECL3), and four intracellular (ICL1-C-terminal tail) domains. ECL and ICL are important for the interaction with OXT and G proteins, respectively, whereas TMs are connected with both functions (7, 11).In contrast to what is observed for placental mammal OXT, OXTR presents hundreds of variants in regulatory and coding regions, including at the intraspecific level. In humans, OXTR single-nucleotide polymorphisms have been associated with several social behavioral phenotypes (14).The presence of OXT-OXTR-related systems throughout the animal kingdom indicates that their typical roles in placental mammals are likely exaptations of ancient functions, such as regulation of fluid balance and egg-laying (15, 16). Studies have attempted to investigate both the interaction of OXT-OXTR-like systems and their coevolution (11, 17). However, our knowledge about this nonapeptide-receptor system, including the extent of its variability in the primate order, remains limited.NWm emerged ∼30 million years ago. They are classified into 16 genera and ∼75 species and present a wide range of reproductive and social behaviors (18, 19), but little is known about their genetic variability and concurrent phenotypic variation (20).The present study reports results about OXT and OXTR diversity in 29 primate species, including 20 NWm species. These analyses include original OXT and OXTR sequences for 16 and 12 NWm species, respectively. We discuss details about the coevolution of these systems, as well as possible connections among reported genetic variability, positive selection, and some key species-specific biologic traits.     

Medication and dosage considerations in the prophylaxis and treatment of high-altitude illness

With increasing numbers of people traveling to high altitude for work or pleasure, there is a reasonable chance that many of these travelers have preexisting medical conditions or are receiving various medications at the time of their sojourn. As with all travelers to high altitude, they are at risk for altitude illnesses such as acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema. While there are clear recommendations for pharmacologic measures to prevent or treat these illnesses, these recommendations are oriented toward healthy individuals and do not take into account the presence of preexisting medical conditions. In this review, we consider how the choice and dose of the medications used in the management of altitude illness-acetazolamide, dexamethasone, nifedipine, tadalafil, sildenafil, and salmeterol-are affected by a patient's underlying medical conditions. We discuss the indications and current dosing recommendations for individuals without underlying disease, and then consider how drug selection or dosing regimens will be affected by the presence of renal insufficiency, hepatic insufficiency, other important medical conditions, and the potential for serious drug interactions. We include comments about interactions with antimalarial medications and antibiotics used in the treatment of traveler's diarrhea, as well as the safety of use during pregnancy. By giving these issues adequate consideration, clinicians can increase the chances that properly evaluated patients with underlying medical conditions will enjoy a safe trip to high altitude.     

Doxycycline prophylaxis for experimental leptospira infection in non-human primates and hamsters

Doxycycline was effective as a chemoprophylactic agent for experimental Leptospira infection in non-human primates and hamsters. Monkeys injected intraperitoneally with Leptospira bataviae, and receiving only diluent as treatment developed a leptospiremia during the first week and later leptospires were cultured from the cerebrospinal fluid and urine. Monkeys treated daily with oral doxycycline for 10 days beginning one day before infection had a shortened period of detectable leptospiremia, and organisms were never detected in the cerebrospinal fluid or urine. Even an oral dose of doxycycline 2 hours before infection and on day 7 prevented the later infection of the cerebrospinal fluid and urine. In hamsters, doxycycline treatment prevented deaths from acute Leptospira infection and when hamsters were treated daily for 4 or more days, renal infection was prevented. The results of animal studies, the susceptibility of LC0475 and the five other isolates to doxycycline in vitro, and lack of evidence for antibiotic resistance in culture suggests this antibiotic may be useful as a prophylactic drug for high risk groups and an effective treatment for leptospirosis in Thailand.     

Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: results of the enoxaparin versus tinzaparin (EVET) trial at 6 months

Background

We have previously reported significant benefits of using enoxaparin, compared to tinzaparin, in the 7- and 30-day incidence of the composite triple end point of death, myocardial infarction (MI), or recurrent angina in patients with non-ST-segment elevation acute coronary syndromes (NSTACS). In the present study, we aimed to determine whether the observed benefits of enoxaparin were maintained beyond the early phase and report the results of the 6-m follow-up of patients in the EVET study.

Methods

We recruited 438 patients with NSTACS. All patients received oral aspirin and were randomized to also receive enoxaparin, 100 IU/kg subcutaneously twice daily (equivalent to 1 mg/kg twice daily; n = 220), or tinzaparin, 175 IU/kg subcutaneously once daily (n = 218), for up to 7 days.

Results

At 6 m, the incidence of the composite triple end point of death, MI, or recurrent angina was lower among patients receiving enoxaparin compared to those receiving tinzaparin (25.5% vs 44.0%, P < .001). A lower incidence of the secondary composite end point of death or MI was also found in the enoxaparin group compared to tinzaparin group (2.7% vs 6.9%, P = .046). The need for revascularization procedures was also lower in the enoxaparin group compared to tinzaparin group (23.2% vs 37.2%, P = .002).

Conclusions

In patients with NSTACS, enoxaparin significantly reduced the rates of recurrent ischemic events and therapeutic procedures in the short term, with sustained benefit at 6 m compared to tinzaparin.     

Pharmaceutical considerations of transdermal nitroglycerin delivery: The various approaches

When formulated as a sublingual or an oral sustained-release dosage form, nitroglycerin has certain shortcomings, i.e., decreased duration of antianginal action and extensive hepatic first-pass elimination, which limit its efficacy. The finding that administration of nitroglycerin in the form of topical ointment decreases the extent of hepatic first-pass elimination and increases the duration of therapeutic activity has pointed the way to the possibility of developing a more effective transdermal drug delivery device. Three such devices are the Nitrodisc, Nitro-Dur, and Transderm-Nitro systems. All three systems generate effective plasma drug levels within 30 minutes and maintain steady-state drug plasma levels as follows: the 16 cm² Nitrodisc at 280.6 ± 18.7 pg/ml for 32 hours; the 20 cm² Nitro-Dur at 201.4 ± 60.7 pg/ml for 24 hours; and the 20 cm² Transderm-Nitro system at 209.8 ± 22.8 pg/ml for 24 hours. In vitro studies show that the drug penetrates the skin with zero-order kinetics in all three systems, the rate for Nitrodisc being 20% greater than that of the other systems. When the daily nitroglycerin dose is calculated in terms of skin permeation rate and the device's surface area, the three transdermal systems become clinically interchangeable.