Secret History: Return of the Black Death Channel 4, 7-8pm In 1348 the Black Death swept through London, killing people within days of the appearance of their first symptoms. Exactly how many died, and why, has long been a mystery. This Secret History documentary follows experts as they pick through the evidence and reveal why the plague killed on such a scale. And they ask, what might be coming next?

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The inorganic anions nitrate (NO3-) and nitrite (NO2-) were previously thought to be inert end products of endogenous nitric oxide (NO) metabolism However, recent studies show that these supposedly inert anions can be recycled in vivo to form NO, representing an important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular in hypoxic states This Review discusses the emerging important biological functions of the nitrate-nitrite-NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration

The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics

Background Despite the popularity of microfracture as a first-line treatment for articular cartilage defects in the knee, systematic information on its clinical efficacy for articular cartilage repair and long-term improvement of knee function is not available. Hypothesis Systematic analysis of the existing clinical literature of microfracture in the knee can improve the understanding of the advantages and limitations of this cartilage repair technique and can help to optimize its indications and clinical outcomes. Study design Systematic review. Methods A comprehensive literature search was performed using established search engines (MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials) to identify original human studies of articular cartilage repair with microfracture. Modified Coleman Methodology Scores were used to analyze the quality of the existing studies. Clinical efficacy of articular cartilage repair was evaluated by systematic analysis of short- and long-term functional outcome scores, macroscopic and microscopic repair cartilage quality, and findings of postoperative magnetic resonance imaging. Results Twenty-eight studies describing 3122 patients were included in the review. The average follow-up was 41 months, with only 5 studies reporting follow-up of 5 years or more. Six studies were randomized controlled trials and the mean Coleman Methodology Score was 58 (range, 22-97). Microfracture effectively improved knee function in all studies during the first 24 months after microfracture, but the reports on durability of the initial functional improvement were conflicting. Several factors were identified that affected clinical outcome. Defect fill on magnetic resonance imaging was highly variable and correlated with functional outcome. Macroscopic repair cartilage quality positively affected long-term failure rate, while the influence of histologic repair tissue quality remained inconclusive. Conclusion This systematic analysis shows that microfracture provides effective short-term functional improvement of knee function but insufficient data are available on its long-term results. Shortcomings of the technique include limited hyaline repair tissue, variable repair cartilage volume, and possible functional deterioration. The quality of the currently available data on micro-fracture is still limited by the variability of results and study designs. Further well-designed studies are needed to determine the long-term efficacy of microfracture and to define its specific clinical indications compared to other cartilage repair techniques.

Clinical Efficacy of the Microfracture Technique for Articular Cartilage Repair in the Knee An Evidence-Based Systematic Analysis

A wide range of nitric oxide (NO)-releasing materials has emerged as potential therapeutics that exploit NO's vast biological roles. Macromolecular NO-releasing scaffolds are particularly promising due to their ability to store and deliver larger NO payloads in a more controlled and effective manner compared to low molecular weight NO donors. While a variety of scaffolds (e.g., particles, dendrimers, and polymers/films) have been cleverly designed, the ultimate clinical utility of most NO-releasing macromolecules remains unrealized. Although not wholly predictive of clinical success, in vitro and in vivo investigations have enabled a preliminary evaluation of the therapeutic potential of such materials. In this tutorial review, we review the application of macromolecular NO therapies for cardiovascular disease, cancer, bacterial infections, and wound healing.

Nitric oxide release: part II. Therapeutic applications.

The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H2 O2 ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi (e.g. responses to α2 -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive Gq (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H2 O2 ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.

Endothelial dysfunction and vascular disease – a 30th anniversary update

Purpose: The purpose of this study was to compare the outcomes of mosaic-type osteochondral autologous transplantation (OAT) and microfracture (MF) procedures for the treatment of the articular cartilage defects of the knee joint in young active athletes. Type of Study: Prospective randomized clinical study. Methods: Between 1998 and 2002, a total of 60 athletes with a mean age of 24.3 years (range, 15 to 40 years) and with a symptomatic lesion of the articular cartilage in the knee were randomized to undergo either an OAT or an MF procedure. Only those athletes playing in competitive sports at regional or national levels were included in the study. Fifty-seven athletes (95%) were available for a follow-up. There were 28 athletes in the OAT group and 29 athletes in the MF group. The mean duration of symptoms was 21.32 ± 5.57 months and the mean follow-up was 37.1 months (range, 36 to 38 months), and none of the athletes had prior surgical interventions to the affected knee. Patients were evaluated using modified Hospital for Special Surgery (HSS) and International Cartilage Repair Society (ICRS) scores, radiograph, magnetic resonance imaging (MRI), and clinical assessment. An independent observer performed a follow-up examination after 6, 12, 24, and 36 months. At 12.4 months postoperatively, arthroscopy with biopsy for histologic evaluation was carried out. A radiologist and a pathologist, both of whom were blinded to each patient's treatment, did the radiologic and histologic evaluations. Results: After 37.1 months, both groups had significant clinical improvement ( P P P = .03; P = .006; P = .006). Younger athletes did better in both groups. No serious complications were reported. There was 1 failure in the OAT group and 9 in the MF group. The ICRS Cartilage Repair Assessment for macroscopic evaluation during arthroscopy at 12.4 months showed excellent or good repairs in 84% after OAT and in 57% after MF. Biopsy specimens were obtained from 58% of the patients and histologic evaluation of repair showed better scores (according to ICRS) for the OAT group ( P Conclusions: At an average of 37.1 months (range, 36 to 38 months) follow-up, our prospective, randomized, clinical study in young active athletes under the age of 40 has shown significant superiority of OAT over MF for the repair of articular cartilage defects in the knee. We found that only 52% of MF athletes could return to sports at the preinjury level. Limitations of our study included a small number of athletes and a relatively short (3-year) follow-up. A long-term follow-up is needed to assess the durability of articular cartilage repair using these methods in young active athletes. Level of Evidence: Level I, Therapeutic study, randomized controlled trial, significant difference (a).

A prospective randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in the knee joint in young athletes.

The purpose of this prospective randomized clinical study was to compare the outcomes of mosaic type autologous osteochondral transplantation (OAT) and microfracture (MF) procedures for the treatment of the articular cartilage defects of the knee joint in athletes. Between 1998 and 2002, a total of 57 athletes with a mean age of 24.3 years and with a symptomatic lesion of the articular cartilage in the knee were randomized to undergo either OAT or MF procedure. There were 28 athletes in OAT group and 29 in MF group. Patients were evaluated using a modified Hospital for Special Surgery (HSS) and International Cartilage Repair Society (ICRS) scores, MRI and clinical assessment after 6, 12, 24 and 36 months after the surgery. According to the modified HSS and ICRS scores, functional and objective assessment showed that 96% had excellent or good results after OAT compared with 52% after MF procedure (P<0.001). In 12, 24 and 36 months after the operations, the HSS and ICRS showed statistically significantly better results in the OAT group (P=0.03; P=0.006; P=0.006). Twenty-six (93%) athletes following OAT and fifteen (52%) athletes following MF returned to sports activities at the preinjury level at an average of 6.5 months (range, 4-8 months) after the operations. At an average of 37.1 months follow-up, our prospective, randomized, clinical study in athletes has shown significant superiority of the OAT over MF for the repair of articular cartilage defects in the knee.

Osteochondral autologous transplantation versus microfracture for the treatment of articular cartilage defects in the knee joint in athletes.

The endothelial cell layer displays the features of a distributed organ and has a variety of biological functions such as keeping the balance between coagulation and fibrinolysis, expression of adhesion molecules for cells in the immune system, metabolism of noradrenaline and 5-hydroxytryptamine, and conversion of angiotensin I and bradykinin. The endothelium also regulates the underlying smooth muscle layer and vascular tone by release of endothelium-derived relaxing factors such as nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF) as well as vasoconstricting factors such as endothelin, superoxide (O(2)(-)), and thromboxane. We have reviewed the nature, mechanisms of action, and role of these factors in regulation of vascular tone, with special emphasis on NO. By a process catalyzed by NO synthase, NO and citrulline is formed from the substrates molecular O(2) and L-arginine. The main receptor for NO is guanylyl cyclase leading to formation of smooth muscle cyclic guanosinmonophosphate and relaxation. EDHF is an endothelium-derived factor causing vasorelaxation of the underlying smooth muscle layer by hyperpolarization. The nature of EDHF is still unknown, but several candidates for EDHF have been proposed such as potassium ions, hydrogen peroxide, and epoxyeicosatrienoic acids. Prostaglandins such as prostacyclin and prostaglandin E2 binds to specific receptors followed by increases in cyclic adenosinmonophosphate and vasorelaxation, while contractile prostaglandins constrict vessels by activation of thromboxane and endoperoxidase receptors. Superoxide anions induce contraction of vascular smooth muscles cells by scavenging NO. Endothelin is a potent endothelium-derived contractile factor. The synthesis of endothelin-1 is induced by hypoxia, thrombin, interleukin-1, transforming growth factor-beta1, vasopressin, and catecholamines. Cardiovascular risk factors like age, hypertension, and hyperlipidemia are associated with impaired endothelium-dependent vasodilation either as a consequence of increased inactivation of endothelium-derived vasodilators or increased formation of endothelium-derived contracting factors. This imbalance of endothelium-derived factors plays a role for development of atheroslerosis and ischemic vascular diseases.

[Role of nitric oxide and other endothelium-derived factors].

Irrational antibiotic use has led society to antibiotic resistance-a serious health problem worldwide. This study aimed to assess public knowledge, beliefs, and behavior concerning antibiotic use and self-medication in Lithuania. The cross-sectional survey method was processed using a validated questionnaire in different regions of Lithuania. In total, 1005 adults completed the questionnaire and were included in the study. More than half of the respondents (61.1%) had poor knowledge of antibiotics. Almost half of the respondents incorrectly identified antibiotics as being effective either against viral (26.0%) or mixed (bacterial and viral) infections (21.7%). The respondents with lower educational qualifications (OR = 2.515; 95% CI 1.464-4.319; p = 0.001) and those from rural areas (OR = 1.765; 95% CI 1.041-2.991; p = 0.035) were significantly less knowledgeable of antibiotics. There was no significant difference between genders, different age groups, or different parenthood status. The determined level of self-medication with antibiotics was 31.0%. The men (OR = 1.650; 95% CI 1.120-2.430; p = 0.011), the respondents from rural areas (OR = 2.002; 95% CI 1.343-2.985; p = 0.001), and those without children (OR = 2.428; 95% CI 1.477-3.991; p < 0.001) were more likely to use antibiotics in self-medication. Lithuanian residents' knowledge of antibiotics is insufficient. More information about antibiotic use should be provided by physicians and pharmacists. Self-medication with antibiotics is a serious problem in Lithuania and requires considerable attention.

Public Knowledge, Beliefs and Behavior on Antibiotic Use and Self-Medication in Lithuania.

Background—Disturbances in pH affect artery function, but the mechanistic background remains controversial. We investigated whether Na+,HCO3− cotransporter NBCn1, by regulating intracellular pH (pHi), influences artery function and blood pressure regulation. Methods and Results—Knockout of NBCn1 in mice eliminated Na+,HCO3− cotransport and caused a lower steady-state pHi in mesenteric artery smooth muscle and endothelial cells in situ evaluated by fluorescence microscopy. Using myography, arteries from NBCn1 knockout mice showed reduced acetylcholine-induced NO-mediated relaxations and lower rho-kinase-dependent norepinephrine-stimulated smooth muscle Ca2+ sensitivity. Acetylcholine-stimulated NO levels (electrode measurements) and N-nitro-l-arginine methyl ester–sensitive l-arginine conversion (radioisotope measurements) were reduced in arteries from NBCn1 knockout mice, whereas relaxation to NO-donor S-nitroso-N-acetylpenicillamine, acetylcholine-induced endothelial Ca2+ responses (fluorescence microsco...

Disruption of Na+,HCO3− Cotransporter NBCn1 (slc4a7) Inhibits NO-Mediated Vasorelaxation, Smooth Muscle Ca2+ Sensitivity, and Hypertension Development in Mice

Edgaras Stankevičius

Papers

A prospective randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in the knee joint in young athletes.

Osteochondral autologous transplantation versus microfracture for the treatment of articular cartilage defects in the knee joint in athletes.

[Role of nitric oxide and other endothelium-derived factors].

Public Knowledge, Beliefs and Behavior on Antibiotic Use and Self-Medication in Lithuania.

Disruption of Na+,HCO3− Cotransporter NBCn1 (slc4a7) Inhibits NO-Mediated Vasorelaxation, Smooth Muscle Ca2+ Sensitivity, and Hypertension Development in Mice