Protective effects of pharmacological therapies in animal models of multiple sclerosis: a review of studies 2014–2019

Multiple sclerosis(MS)is an inflammatory demyelinating disease of the central nervous system.The disability caused by inflammatory demyelination clinically dominates the early stages of relapsing-remitting MS and is reversible.Once there is considerable loss of axons,MS patients enter a secondary progressive stage.Disease-modifying drugs currently in use for MS suppress the immune system and reduce relapse rates but are not effective in the progressive stage.Various animal models of MS(mostly mouse and rat)have been established and proved useful in studying the disease process and response to therapy.The experimental autoimmune encephalomyelitis animal studies reviewed here showed that a chronic progressive disease can be induced by immunization with appropriate amounts of myelin oligodendrocyte glycoprotein together with mycobacterium tuberculosis and pertussis toxin in Freund's adjuvant.The clinical manifestations of autoimmune encephalomyelitis disease were prevented or reduced by treatment with certain pharmacological agents given prior to,at,or after peak disease,and the agents had protective effects as shown by inhibiting demyelination and damage to neurons,axons and oligodendrocytes.In the cuprizone-induced toxicity animal studies,the pharmacological agents tested were able to promote remyelination and increase the number of oligodendrocytes when administered therapeutically or prophylactically.A monoclonal IgM antibody protected axons in the spinal cord and preserved motor function in animals inoculated with Theiler's murine encephalomyelitis virus.In all these studies the pharmacological agents were administered singly.A combination therapy may be more effective,especially using agents that target neuroinflammation and neurodegeneration,as they may exert synergistic actions.     

Estrogen receptor GPR30 reduces oxidative stress and proteinuria in the salt-sensitive female mRen2.Lewis rat

The current study assessed whether activation of the novel estrogen receptor GPR30 ameliorates salt-dependent renal damage in intact mRen2.Lewis (mRen2) females. Hemizygous mRen2 rats were maintained on either a normal salt (0.5% Na) or high-salt (HS; 4.0% Na) diet for 10 weeks (5 to 15 weeks of age), and HS animals were treated with the GPR30 agonist G-1 or vehicle for 2 weeks. Systolic blood pressure markedly increased with HS diet (149±3 to 219±5 mm Hg; P<0.01), but G-1 did not influence pressure (P=0.42). G-1 and estradiol induced relaxation of preconstricted mesenteric vessels from normal salt mRen2 rats, but both responses were attenuated in the HS group. Despite the lack of an effect on blood pressure, G-1 decreased renal hypertrophy, proteinuria, urinary 8-isoprostane excretion, and tubular 4-hydroxynonenal staining. HS diet significantly increased GPR30 mRNA (1.01±0.04 versus 1.59±0.13; P<0.01) and protein (0.60±0.31 versus 3.99±0.75; P<0.01) in the renal cortex. GPR30 was highly expressed in the brush border of proximal tubules and colocalized with megalin. Finally, megalin expression was reduced by HS diet and restored with G-1. We conclude that GPR30-mediated beneficial effects in salt-sensitive mRen2 females occurred independent of changes in systolic blood pressure. The failure of G-1 to influence pressure may reflect a salt-induced impairment in GPR30-mediated vasorelaxation. The renoprotective actions of GPR30 may involve attenuation of tubular oxidative stress and activation of megalin-mediated protein reabsorption.     

Disentangling Family Life and Hair Pulling: Trichotillomania and Relatedness

ABSTRACT

Trichotillomania (hair pulling) remains a relatively unknown form of body-focused repetitive behavior (BFRB). Sufferers tend to conceal both the action and its effects from others because of stigmatization, which is strong in both public and domestic spheres. Negative responses from close family members can add significantly to the suffering. Based on fieldwork in the United Kingdom and United States, we explore how hair pulling troubles ties even among close family members. We show why ethnographic methods reveal impacts of hair pulling that structured assessments do not yet capture and argue for a more nuanced study of BFRBs through anthropologies of relatedness.     

Evidence Supporting Couple-Based Interventions for the Recovery of Sexual Intimacy After Prostate Cancer Treatment

Purpose of the Review

During the past 10 years, interventions supporting couples’ sexual recovery after prostate cancer treatment have been developed and tested. We sought to review these intervention studies to determine the degree to which they have been effective.

Recent Findings

Eleven studies (4 pilot studies and 7 randomized controlled trials) were reviewed. Our findings suggest that outcomes, such as sexual function, relationship satisfaction, or intimacy, are minimally improved. However, the interventions succeed in increasing couples’ knowledge of the treatment-related sexual side effects and rehabilitation, men’s use of ED treatments, partners’ attitudes to ED, and couples’ maintenance of sexual engagement.

Summary

Based on the findings, we propose that further research on couple-based interventions continue to identify meaningful outcomes sensitive to change with the goal of protecting couples from losing sexual relationships despite treatment-related functional losses. An analytic approach that measures patient-partner mutual influence on outcomes is also recommended.

     

Cell membrane and mitotic markers show that the neonatal rat gubernaculum grows in a similar way to an embryonic limb bud

Aim/Background

How the gubernaculum guides the testis into the scrotum remains controversial, with various proposals from passive inversion to active growth. We aimed to determine if the gubernaculum contains an area of active proliferation, such as a “progress zone” in a growing embryonic limb bud, using a fluorescent cell membrane marker, 1,1′-didodecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate [DiIC₁₂(3)], to trace cell migration, and 5-bromodeoxyuridine (BUDR) (a thymidine analogue) as a mitotic marker.

Methods

Gubernacula were collected from neonatal male rats (n = 42, day 1-2, Sprague-Dawley) and cultured with calcitonin gene-related peptide (CGRP; 714 nmol/L). 1,1′-didodecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate-coated glass beads (diameter, 150-212 μm) were placed next to the bulb for the first 3 hours. Gubernacula were cultured for 3, 18, and 24 hours, then frozen sections cut and examined by confocal microscopy (wavelength, 549 nm). In a second experiment, pups not exposed to exogenous CGRP (n = 53, day 0, Sprague-Dawley) were injected intraperitoneally with BUDR (50 mg/kg of body weight); gubernacula were collected at 2, 48, 72, and 96 hours postinjection (PI), sectioned, and stained using immunohistochemistry to count the number of BUDR-positive cells per 100 cells (labeling index) in the bulb, cremaster, cord, and epididymis.

Results

After 24 hours' culture with CGRP, the bulb showed an oval region (diameter, 300 μm) of high fluorescence, and the cremaster region showed elongated cells migrating out of the bulb. When cultured without CGRP, the same oval region contained no fluorescence. In vivo BUDR labeling index increased in all areas until 48 hours postinjection and then decreased most rapidly in the bulb (P < .05), in the presence of endogenous CGRP from the genitofemoral nerve.

Conclusions

The rat gubernaculum contains a putative progress zone, such as in a growing limb bud, in the presence of CGRP. Cells migrate out of this zone to form cremaster muscle. We hypothesize that proliferation in the bulb elongates the gubernaculum, whereas proliferation of cremaster cells would increase gubernacular diameter. This brings to “life” the gubernaculum as an actively growing organ in contrast to the inert ligament connecting the testis to the scrotum portrayed in most anatomy textbooks.     

Follow-up After Curative Resection of Colorectal Cancer

Of the 13.7 million cancer survivors living in the United States as of January 2012, 1.2 million, or 9 %, were colorectal cancer (CRC) survivors. Determining an optimal surveillance for CRC survivors is necessary because of the significant burden follow-up poses to patients, physicians, and the health care system. Currently, there is no consensus regarding optimal follow-up in CRC patients. Current literature and published guidelines related to CRC follow-up were reviewed to examine the evidence for the surveillance strategies and specific tools demonstrated to improve outcome after curative CRC resection. An intensive surveillance strategy results in increased identification of recurrences amenable to curative resection but does not result in reduced overall or CRC-specific mortality. Patients most likely to benefit from surveillance include younger patients, those with earlier tumors, locoregional recurrences, longer time to recurrence, lower carcinoembryonic antigen (CEA) levels before reoperation, and those with isolated recurrence. Complete resection of recurrence is the only factor consistently associated with improved survival. CEA, colonoscopy, and liver-focused imaging surveillance appear to have the greatest impact on mortality after curative CRC resection. A CRC surveillance strategy is recommended that includes tumor risk stratification, that provides a focus on identifying recurrences amenable to complete resection, and that utilizes those modalities demonstrated to be most effective at improving outcome after CRC resection.     

Balancing high accrual and ethical recruitment in paediatric oncology: a qualitative study of the 'look and feel' of clinical trial discussions

Background  

High accrual to clinical trials enables new treatment strategies to be tested rapidly, accurately and with generalisability. Ethical standards also must be high so that participation is voluntary and informed. However, this can be difficult to achieve in trials with complex designs and in those which are closely embedded in clinical practice. Optimal recruitment requires a balance of both ethical and accrual considerations. In the context of a trial of stratified treatments for children with acute lymphoblastic leukaemia (UKALL2003) we examined how recruitment looked to an observer and how it felt to the parents, to identify how doctors' communication could promote or inhibit optimal recruitment.