Efficacy of cefmetazole in immunocompetent patients with uncomplicated colonic diverticulitis: A propensity score matching analysis.

INTRODUCTION: The incidence of colonic diverticulitis is increasing in Japan. Although antimicrobial chemotherapy is a treatment option, Japanese guidelines for diverticulosis do not recommend any antibiotic in particular and antibiotic selection is left to the discretion of the prescribing physician, who often selects antibiotics with anti-pseudomonal activity. Therefore, this study compared the efficacy of cefmetazole (CMZ) with that of tazobactam/piperacillin (TAZ/PIPC) in hospitalized Japanese immunocompetent patients with uncomplicated colonic diverticulitis. PATIENTS AND METHODS: This retrospective study included Japanese immunocompetent patients hospitalized for colonic diverticulitis between April 2019 and March 2022. Participants were divided into the CMZ and TAZ/PIPC groups. After propensity score matching, the intergroup differences in clinical outcomes, including adverse events, mortality, and re-admission rate, were ascertained. RESULTS: During the study period, 142 Japanese patients were hospitalized with community-onset colonic diverticulitis; 124 of these patients were immunocompetent. Of the 124 patients, 42 were excluded, and the CMZ and TAZ/PIPC groups comprised 62 and 20 patients, respectively. After propensity score matching, there were 16 patients in each group. There was no significant intergroup difference in the mortality and re-admission rates; however, the incidence of liver dysfunction was significantly higher (p = 0.018) in the TAZ/PIPC group. CONCLUSION: In patients with colonic diverticulitis, CMZ therapy should be selected because of the adequate clinical outcomes and lower incidence of adverse events, as this would reduce broad-spectrum antibiotic use and minimize antibiotic-resistant bacteria.

Involvement of thyrotropin in photoperiodic signal transduction in mice.

Local thyroid hormone catabolism within the mediobasal hypothalamus (MBH) by thyroid hormone-activating (DIO2) and -inactivating (DIO3) enzymes regulates seasonal reproduction in birds and mammals. Recent functional genomics analysis in birds has shown that long days induce thyroid-stimulating hormone production in the pars tuberalis (PT) of the pituitary gland, which triggers DIO2 expression in the ependymal cells (EC) of the MBH. In mammals, nocturnal melatonin secretion provides an endocrine signal of the photoperiod to the PT that contains melatonin receptors in high density, but the interface between the melatonin signal perceived in the PT and the thyroid hormone levels in the MBH remains unclear. Here we provide evidence in mice that TSH participates in this photoperiodic signal transduction. Although most mouse strains are considered to be nonseasonal, a robust photoperiodic response comprising induced expression of TSHB (TSH beta subunit), CGA (TSH alpha subunit), and DIO2, and reduced expression of DIO3, was observed in melatonin-proficient CBA/N mice. These responses could not be elicited in melatonin-deficient C57BL/6J, but treatment of C57BL/6J mice with exogenous melatonin elicited similar effects on the expression of the above-mentioned genes as observed in CBA/N after transfer to short-day conditions. The EC was found to express TSH receptor (TSHR), and ICV injection of TSH induced DIO2 expression. Finally, we show that melatonin administration did not affect the expression of TSHB, DIO2, and DIO3 in TSHR-null mice. Taken together, our findings suggest that melatonin-dependent regulation of thyroid hormone levels in the MBH appears to involve TSH in mammals.

Thyrotoropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction.

Attention deficit/hyperactivity disorder (ADHD) has been reported in association with resistance to thyroid hormone, a disease caused by a mutation in the thyroid hormone receptor ß (TRß) gene. TRß is a key protein mediating down-regulation of thyrotropin (TSH) expression by 3,3',5-tri-iodothyronine (T3), an active form of thyroid hormone. Dysregulation of TSH and its receptor (TSHR) is implicated in the pathophysiology of ADHD but the role of TSHR remains elusive. Here, we clarified a novel role for TSHR in emotional and cognitive functions related to monoaminergic nervous systems. TSHR knockout mice showed phenotypes of ADHD such as hyperactivity, impulsiveness, a decrease in sociality and increase in aggression, and an impairment of short-term memory and object recognition memory. Administration of methylphenidate (1, 5 and 10mg/kg) reversed impulsiveness, aggression and object recognition memory impairment. In the knockout mice, monoaminergic changes including decrease in the ratio of 3-methoxy-4-hydroxyphenylglycol/noradrenaline and increase in the ratio of homovanillic acid/dopamine were observed in some brain regions, accompanied by increase in the expression of noradrenaline transporter in the frontal cortex. When TSH was completely suppressed by the supraphysiological administration of T3 to the adult mice, some behavioral and neurological changes in TSHR KO mice were also observed, suggesting that these changes were not due to developmental hypothyroidism induced by the inactivation of TSHR but to the loss of the TSH-TSHR pathway itself. Taken together, the present findings suggest a novel role for TSHR in behavioral and neurological phenotypes of ADHD.

Tissue-specific posttranslational modification allows functional targeting of thyrotropin.

Thyroid-stimulating hormone (TSH; thyrotropin) is a glycoprotein secreted from the pituitary gland. Pars distalis-derived TSH (PD-TSH) stimulates the thyroid gland to produce thyroid hormones (THs), whereas pars tuberalis-derived TSH (PT-TSH) acts on the hypothalamus to regulate seasonal physiology and behavior. However, it had not been clear how these two TSHs avoid functional crosstalk. Here, we show that this regulation is mediated by tissue-specific glycosylation. Although PT-TSH is released into the circulation, it does not stimulate the thyroid gland. PD-TSH is known to have sulfated biantennary N-glycans, and sulfated TSH is rapidly metabolized in the liver. In contrast, PT-TSH has sialylated multibranched N-glycans; in the circulation, it forms the macro-TSH complex with immunoglobulin or albumin, resulting in the loss of its bioactivity. Glycosylation is fundamental to a wide range of biological processes. This report demonstrates its involvement in preventing functional crosstalk of signaling molecules in the body.

Design of two-tooth unidirectional rotary-ratchet molecular machines driven by linearly polarized ac fields.

An artificial molecular rotor system mounted in a biological membrane, which can unidirectionally rotate in response to weak pumping from a linearly polarized ac field, is modeled. The dynamics of the rotor unit are described by the Langevin equation for a particle in a two-dimensional bistable potential with a two-tooth ratchet structure. This model reveals effects due to the two-dimensionality of the ratchet and the polarization of the applied field. First, we demonstrate that a unidirectional rotation appears with stochastic resonance exhibiting a bell-shaped peak for noise intensity in the mean angular momentum (MAM) of the rotor. An analytical expression for the MAM, (L), is obtained on the basis of a four-state Markov approximation. Second, a significant effect due to torsional nonlinearity (representing the ratchet-like structure) in the potential geometry is quantified: in the absence of torsion, the MAM depends on the polarization angle φ of the applied field as (L) sin(2φ), whereas in the presence of torsion, an additional bias appears in the MAM as (L)(bias + sin(2φ)). It is found that this effect can be used to make the rotor system robustly maintain rotation in a single direction independent of the mounting conditions. Possible designs for an artificial molecular rotor system using the torsion effect are discussed.