Inhibitory effect of the 4-aminotetrahydroquinoline derivatives, selective chemoattractant receptor-homologous molecule expressed on T helper 2 cell antagonists, on eosinophil migration induced by prostaglandin D2

Prostaglandin (PG) D2, a major cyclooxygenase metabolite generated from immunologically stimulated mast cells, is known to induce activation and chemotaxis in eosinophils, basophils, and T helper 2 (Th2) lymphocytes via a newly identified PGD2 receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). CRTH2 is hypothesized to play an important role in the outcome of allergic responses. However, the absence of selective CRTH2 antagonists has prevented the elucidation of the role of CRTH2 in pathogenesis of allergic diseases. We now report compounds discovered as selective CRTH2 antagonists, (2R*,4S*)-N-(1-benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylisobutyramide (K117) and (2R*,4S*)-N-(1-benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylcyclopropanecarboxamide (K604). K117 and K604 have inhibitory effects on human CRTH2 with Ki values of 5.5 and 11 nM, respectively. The effect of these compounds is CRTH2-specific with no cross-reactivity against 15 other receptors and four arachidonic acid-metabolizing enzymes. K117 and K604 has no effect on the basal Ca2+ level and inhibited the Ca2+ response induced by PGD2 in 293EBNA cells expressing human CRTH2. Also, K117 and K604 inhibit PGD2-induced human eosinophil chemotaxis with IC50 values of 7.8 and 42.2 nM, respectively, but they do not inhibit the CC-chemokine receptor 3 agonist eotaxin-induced chemotaxis. These results indicate that K117 and K604 are highly potent and selective antagonists for human CRTH2. These compounds have possibilities to become useful tools to explore CRTH2 functions in allergic diseases.     

Characteristics of prolidase from the erythrocytes of normal humans and patients with prolidase deficiency and their mother.

Prolidases I and II were highly purified from human erythrocytes. The effects of various amino acids, MnCl2 and mercaptoethanol, on these two enzymes were investigated. Normal prolidase II was very labile in the absence of MnCl2 or mercaptoethanol. The activity of prolidase II was maintained at about 76% by pre-incubation with MnCl2; it was then activated up to 140% by treatment with mercaptoethanol for 60 minutes at 37 degrees C. Normal prolidases I and II showed the highest activity against glycylproline or methionylproline in the presence of MnCl2. The activity of prolidase I against glycylproline was enhanced strongly by glycine and MnCl2, but not activated in the absence of MnCl2. The activity of prolidase II against methionylproline was enhanced three-fold in the presence of glycine and MnCl2, but its activity against glycylproline was very low even in the presence of MnCl2. A stronger enhancement of this activity was found in normal erythrocytes, and a lower level of this activity was found in erythrocytes of patients treated with glycine, MnCl2 and mercaptoethanol compared to those treated with glycine and MnCl2. The activity of prolidase II against methionylproline in all erythrocytes, of normal humans and of patients, was strongly activated by the addition of glycine with MnCl2 but suppressed by the addition of mercaptoethanol.     

Postoperative tetanus after laparoscopic obturator hernia repair for strangulated ileus: report of a case

This report presents the case of an 84-year-old woman who developed tetanus 3 days after the resection of a gangrenous small intestine caused by obturator hernia incarceration. The diagnosis of tetanus was clinically made after the appearance of generalized spastic contractions with opisthotonus. Clostridium tetani organisms residing in the gastrointestinal tract were presumed to have been endogenously inoculated into the strangulated intestine, where it produced tetanospasmin, causing tetanus. The patient successfully recovered after aggressive intensive care. There have been 16 case reports of tetanus occurring after gastrointestinal surgical procedures. Primary care physicians should thus be aware of the fact that, although extremely rare, C. tetani residing in the gastrointestinal tract can provide a possible endogenous source of tetanus infection.     

Tuberculosis treatment default among HIV-TB co-infected patients in urban Uganda

Objective To identify health facility and patient‐specific factors associated with TB treatment default in HIV‐infected patients, in a TB clinic on the campus of Mulago National Referral Hospital in Kampala, Uganda. Methods Unmatched case–control study between March and May 2009. Cases were TB patients known to have defaulted on their anti‐TB treatment, defined as a TB patient who had documented discontinuation of TB medication for two or more consecutive months due to reasons other than physician’s advice and who did not access care at another facility. Controls were TB patients who completed 8 months of anti‐TB treatment without interruption of two or more months. Data on health facility‐specific factors and individual characteristics were collected using semi‐structured questionnaires. Results Factors associated with defaulting from TB treatment were: distance from home to clinic (OR 2.22; 1.21–4.06); long waiting time at the clinic (OR 4.18; 2.18–8.02); poor drug availability (OR 4.75; 2.29–9.84); conduct of staff (OR 2.72; 1.02–7.25); lack of opportunity to express feelings (OR 3.47; 1.67–7.21). Other patient‐related factors were lack of health education, i.e. not being aware of the duration of treatment or the risk of discontinuing it (OR 5.31; 1.94–14.57); not knowing that TB can be cured (OR 44.11; 13.66–142.41); length of TB treatment (OR 10.77; 5.18–22.41), and side effects of treatment OR 5.53 (2.25–13.61). Conclusions Defaulting is influenced by health systems, staff factors, and patient misinformation. Health education on TB directed at patients combined with staff sensitization could help to improve adherence to TB treatment.     

Paravascular inner retinal abnormalities in healthy eyes

Graefe's Archive for Clinical and Experimental Ophthalmology - To investigate the prevalence and characteristics of paravascular inner retinal abnormalities in healthy eyes. In this prospective...     

Dynamic Changes of the Mitochondria in Psychiatric Illnesses: New Mechanistic Insights From Human Neuronal Models

Mitochondria play a crucial role in neuronal function, especially in energy production, the generation of reactive oxygen species, and calcium signaling. Multiple lines of evidence have suggested the possible involvement of mitochondrial deficits in major psychiatric disorders, such as schizophrenia and bipolar disorder. This review will outline the current understanding of the physiological role of mitochondria and their dysfunction under pathological conditions, particularly in psychiatric disorders. The current knowledge about mitochondrial deficits in these disorders is somewhat limited because of the lack of effective methods to dissect dynamic changes in functional deficits that are directly associated with psychiatric conditions. Human neuronal cell model systems have been dramatically developed in recent years with the use of stem cell technology, and these systems may be key tools for overcoming this dilemma and improving our understanding of the dynamic changes in the mitochondrial deficits in patients with psychiatric disorders. We introduce recent discoveries from new experimental models and conclude the discussion by referring to future perspectives. We emphasize the significance of combining studies of human neuronal cell models with those of other experimental systems, including animal models.     

Investigation and Macroscopic Anatomical Study of Referred Pain in Patients with Hip Disease

[Purpose] The aim of this study was to examine the incidence and patterns of referred pain in patients with hip disease, as well as the nerve distribution in the hip and knee joints of 2 cadavers. [Subjects and Methods] A total of 113 patients with hip joint disease were included in the investigation. The incidence of regional pain and referred pain patterns were evaluated before and after arthroplasty. Two cadavers were macroscopically observed to verify the nerve innervation of the hip and knee joints. [Results] Anterior knee pain was observed preoperatively in 13.3% (in resting) and 33.6% (in motion) of the patients, which was comparable with the incidence of greater trochanter pain. In addition, the preoperative incidence rates of knee pain in resting and motion markedly decreased postoperatively. Of note is the remarkable incidence of pain radiating to the ventral lower limb. An anteromedial innervation was determined in the cadavers by the articular branches of the obturator and femoral nerve, which supply small branches to the knee joints. [Conclusion] Our results suggest that the distribution of the incidence of pain among the patients with hip disease is diverse owing to the sensory distribution of the femoral and obturator nerves.Key words: Hip joint disease, Referred pain, Macroscopic anatomy