Proposal of a Parameter for OATP1B1 Inhibition Screening at the Early Drug Discovery Stage

It is known that potent inhibition of organic-anion-transporting polypeptide (OATP)1B1 increases exposure to statins, leading to severe adverse effects. The aim of this study was to propose a parameter and its criteria in OATP1B1 inhibition assay at the early drug discovery stage to avoid compounds with the risk of statin-related adverse effects. According to drug label information, most compounds classified as “contraindicated” or “should be avoided” when administered concomitantly with statins increased their AUCs more than 4-fold. Generally, R values where R = 1 + plasma unbound fraction (fu) × maximum inhibitor concentration at the inlet to the liver/IC₅₀ are used to evaluate the extent of clinical drug interaction. However, clinical doses and C_max cannot be determined at the screening stage. Therefore, we estimated the correlations between change in AUC of statins concomitantly administered with OATP1B1 inhibitors and various parameters including fu/IC₅₀. Cyclosporin A, rifampicin, and telaprevir increased the AUC of statins more than 4-fold and fu/IC₅₀ of these compounds was >0.1 L/μmol. On the other hand, fu/IC₅₀ of other compounds was ≤0.03 L/μmol. This study indicates that fu/IC₅₀ is a useful parameter to avoid compounds that seriously affect statin potency through interaction with OATP1B1 at the screening stage.     

Repeated embolization of intercostal arteries after blunt chest injury

To deal with an arterial bleeding from the chest wall after a blunt chest injury, embolization of the bleeding arteries can be a valuable therapeutic option, which is less invasive than a thoracotomy. However, its results are variable, being highly operator-dependent. In the present case, we performed successful emergency embolization of the 4th and 5th intercostal arteries for persistent hemorrhage following blunt trauma to the chest. Several days after the first embolization, secondary embolization was required for treating a pseudoaneurysm that was formed in the 5th intercostal artery. Although the mechanisms underlying pseudoaneurysm formation are not clearly understood, its rupture is potentially fatal. Therefore, it is essential to carefully follow-up patients who experience blunt chest injury to avoid this serious complication.     

Development of takotsubo cardiomyopathy with severe pulmonary edema before a cesarean section

Takotsubo cardiomyopathy is an acute syndrome involving apical ballooning and consequent dysfunction of the left ventricle. Most cases of left ventricular dysfunction resolve within 1 month. We present the case of a 40-year-old woman who developed severe heart failure caused by takotsubo cardiomyopathy with severe left ventricular dysfunction during the perinatal period. Because of the presence of multiple myomas, she was scheduled to undergo a cesarean section under general anesthesia. However, after induction of general anesthesia, she had to be awakened because of the presence of a difficult airway. Because she exhibited insufficient oxygenation, she was transferred to the emergency center. Upon hospital admission, she expectorated large amounts of pink sputum, indicating severe pulmonary edema. Cesarean section was performed immediately. Echocardiography revealed severe left ventricular dysfunction. Full recovery of cardiac function required almost 1 month, after which she was discharged from the hospital without further complications. This is the first reported case of takotsubo cardiomyopathy induced by a failed intubation during a scheduled cesarean section. Takotsubo cardiomyopathy usually shows a good prognosis, but if this myopathy develops during the perinatal period, it can worsen because of excessive preload following the termination of fetoplacental circulation.     

Protective properties of a fusion pneumococcal surface protein A (PspA) vaccine against pneumococcal challenge by five different PspA clades in mice

An increase in the appearance of nonvaccine serotypes in both children and adults with invasive pneumococcal disease (IPD) after introduction of pneumococcal conjugate vaccine represents a limitation of this vaccine. In this study, we generated three recombinant pneumococcal surface protein A (PspA) proteins comprising PspA families 1 and 2, and we examined the reactivity of antisera raised in mice immunized with a PspA fusion protein in combination with CpG oligonucleotides plus aluminum hydroxide gel. The protective effects of immunization with PspA fusion proteins against pneumococcal challenge by strains with five different PspA clades were also examined in mice. Flow cytometry demonstrated that PspA3+2-induced antiserum showed the greatest binding of PspA-specific IgG to all five challenge strains with different clades. PspA2+4- or PspA2+5-induced antiserum showed the lowest binding of PspA-specific IgG to clade 3. Immunization with PspA3+2 afforded significant protection against pneumococcal challenge by five strains with different clades in mice, but immunization with PspA2+4 or PspA2+5 failed to protect mice from pneumococcal challenge by strains with clades 1 and 3. The binding of PspA-specific IgG in antisera raised by three PspA fusion proteins was examined in 68 clinical isolates from adult patients with IPD. Immunization of mice with PspA3+2-induced antiserum with a high binding capacity for clinical isolates expressing clades 1–4, but not clade 5. Our results suggest that the PspA3+2 vaccine has an advantage over the PspA2+4 or PspA2+5 vaccine in terms of a broad range of cross-reactivity with clinical isolates and cross-protection against pneumococcal challenge in mice.     

A biochemical study of the distribution of collagen and its crosslinks in knee ligaments and the patellar tendon

Purpose: The purpose of this study was to investigate biochemical differences in collagen crosslinks from different locations within the ligaments and a tendon of the human knee.

Materials and Methods: The anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), lateral collateral ligament (LCL), and patellar tendon (PT) were obtained from 24 cadavers (13 men and 11 women) whose average age at the time of death was 84.8 years. Ligaments and PT samples were obtained from the femoral and tibial insertions and the midsubstance. Hydroxyproline (Hyp) and collagen crosslinks, including pyridinoline (Pyr) and pentosidine (Pen), were compared among the different sites.

Results: The midsubstance Hyp concentration was greater than at the femoral and tibial insertions in the ACL (p?=?0.00124 and 0.000255, respectively) and PCL (p?=?0.00036 and 0.042, respectively). The Pyr:collagen ratio did not differ among sites in any of the ligaments or PT. The Pen:collagen ratio at the midsubstance was greater than at the femoral and tibial insertions in the ACL (p?=?0.00022 and 0.00025, respectively) and LCL (p?=?0.000081 and 0.000021, respectively) and was greater at the femoral insertion in the MCL (p?=?0.00010).

Conclusions: The mature collagen crosslink Pyr was not different in distribution in knee ligaments and the PT. Pen increased at the midsubstance ligaments and the PT. As increased Pen may represent ligament degeneration, this may indicate that degeneration may progress more rapidly at the midsubstance than at the insertion sites of a ligament.     

Sialolithiasis in two areas of the upper lip

Objective

Minor salivary gland sialolithiasis occurs in ~1 % of all sialolithiasis cases. We report a case of sialolithiasis considered to have occurred in the minor salivary gland in two areas of the upper lip, with special emphasis on the findings from image examinations.

Case report

A 33-year-old male complained of a painless mass on the left upper lip. At the first examination, there was a nodular, hard swelling that involved the left cuspid area of the upper lip. Although a panoramic radiograph revealed no abnormality, an intraoral radiograph showed a small radiopaque body with a laminar pattern. Computed tomography images indicated that a calcified body was present in two areas of the upper lip. On magnetic resonance imaging, the lesion was observed as a lower-signal area than the surrounding soft tissue. The mass had a high signal in the central area in the T2 and short T1 inversion recovery images. The sonogram showed a hypoechoic mass with an echogenic structure in the central area. An excisional biopsy of the left upper lip was performed under local anesthesia. A well-demarcated mass with a calcified body was enucleated. The histopathologic diagnosis was sialoadenitis with sialolithiasis.

Conclusion

Most cases of minor salivary gland sialolithiasis are solitary, with multiple sialolithiasis being extremely rare. Sonograms are useful in the diagnosis of minor salivary gland sialolithiasis. Careful imaging examination is necessary to identify multiple lesions and select appropriate treatments.     

Understanding the immunopathogenesis of COVID-19: Its implication for therapeutic strategy

Although 80% of individuals infected with the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) recover without antiviral treatments, the other 20% progress to severe forms of pulmonary disease, suggesting that the host’s immune response to the virus could influence the outcome of coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects alveolar epithelial type 2 cells expressing angiotensin-converting enzyme 2, and these infected epithelial cells recruit dendritic cells, neutrophils and monocytes /macrophages, leading to the activation of CD4+ and CD8+ T cells. These cells launch an antiviral immune response, but are able to completely suppress viral replication or completely eradicate virus in a limited proportion of infected patients. In other patients, viral suppression is incomplete and the numbers of circulating B and T cells are subsequently reduced by as yet unknown mechanisms. Some patients with sustained viral replication progress to a severe condition called cytokine storm. Although antiviral drug(s) should be considered early in infection to prevent progression, there have been no antiviral therapies proven to be effective for significantly inhibiting the viral replication in vivo and suppressing the progression to cytokine storm. Blocking the action of cytokines with dexamethasone or anti-interleukin-6 could have a pivotal role in treatment of those patients. Therapeutic strategy should therefore be based on viral kinetics and the immunopathology of COVID-19.