The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, chemical, thermal, and electrical stimuli.

The role of excitatory amino acids (EAAs) in the excitation of monkey spinothalamic tract (STT) neurons following activation of cutaneous primary afferent fibers by noxious and non-noxious stimuli was investigated. The responses of STT neurons to either NMDA or non-NMDA EAA ligands were blocked by infusion of specific antagonists through a microdialysis fiber into the region surrounding the cells. Our results show that blockade of non-NMDA receptors results in a nearly complete elimination of the responses of STT neurons to all stimuli. Blockade of NMDA receptors results in an attenuation of the responses to noxious stimuli but, in addition, prevents the development of the sensitization of STT neurons that is often observed after intradermal injection of capsaicin. These observations further support a role of EAAs in the transmission of sensory information from primary afferent fibers to dorsal horn neurons and a role for NMDA receptors in the generation of hyperalgesia.     

Buflomedil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in peripheral and cerebral vascular diseases

Buflomedil hydrochloride is a vasoactive drug with a variety of pharmacodynamic properties. Importantly, it seems to improve nutritional blood flow in ischaemic tissue of patients with peripheral and/or cerebral vascular disease by a combination of pharmacological effects: inhibition of alpha-adrenoceptors, inhibition of platelet aggregation, improved erythrocyte deformability, nonspecific and weak calcium antagonistic effects, and oxygen sparing activity. Therapeutic trials with buflomedil in patients with peripheral vascular diseases have shown that it increases walking distances in those with intermittent claudication and heals trophic lesions and reduces rest pain in many patients with more severe vasculopathies. In open clinical trials a good to very good clinical response was achieved in 57 to 87% of those treated. In comparative studies buflomedil 600 mg/day orally was shown to be significantly superior to placebo and comparable in efficacy to pentoxifylline (oxpentifylline) and naftidrofuryl. In patients with symptoms presumed to be due to cerebrovascular insufficiencies and elderly patients with senile dementia, buflomedil 450 to 600 mg/day alleviated symptoms associated with impairment of cognitive and psychometric function and was significantly superior to placebo and slightly more effective than drugs such as cinnarizine, flunarizine and co-dergocrine mesylate. Overall, buflomedil at dosages of up to 600 mg/day has been very well tolerated and discontinuation of therapy has rarely been necessary. Thus, buflomedil would seem to be a useful adjunct to conservative treatment in patients with mild-to-moderate peripheral vascular disease and/or cerebrovascular insufficiency, and well worth a try in patients with more severe peripheral disease unable to undergo surgery. However, a few well-designed long term studies are needed to fully define its overall place in therapy.     

Hormones and the immunological capacity. V. Modification of growth hormone-producing cells in the adenohypophysis of neonatally thymectomized germ-free mice: an electron microscopical study

An electron microscopical study has been carried out to evaluate the effect of neonatal thymectomy on the hypophysis of germ-free mice at different times after the operation. The results fully confirm the previous findings in neonatally thymectomized, conventional mice. Also neonatal thymectomy in germ-free mice results in degranulation of growth hormone-producing cells in the anterior pituitary gland. A large number of these cells show an enlarged endoplasmic reticulum with formation of cisternae and loss of hormone granuli. This alteration of growth hormone-producing cells is similar to that observed in other cells of the hypophysis after removal of other target glands such as thyroid or gonads. The changes in the growth hormone-producing cells in neonatally thymectomized germ-free mice occur even in the first days after birth, when the number of differentiated growth hormone-producing cells is still very low.

Some thymectomized germ-free mice showed symptoms of the wasting syndrome but the alterations in their hypophysis were not more pronounced than those observed in thymectomized germ-free but nonwasting mice. The data fit well our suggestion that the perinatal thymus is under hypophysial control and that immunological maturation depends on endocrine function.

     

Hormones and the immunological capacity. III. The immunodeficiency disease of the hypopituitary Snell-Bogg dwarf mouse

The naturally occurring immunodeficiency syndrome of the hypopituitary Snell-Bagg dwarf mice has been characterized. The immunopathological aspects of this syndrome derive primarily from an arrested ontogenetic development of the thymus. The alteration of the thymus function is caused by the failure of the pituitary to produce certain hormones, especially somatotropic hormone. The relation of this syndrome of the dwarf mouse to human immunodeficiency diseases and endocrinopathies is discussed.     

Increased 1,25(OH)2-Vitamin D Concentrations after Energy Restriction Are Associated with Changes in Skeletal Muscle Phenotype

The influence of energy restriction (ER) on muscle is controversial, and the mechanisms are not well understood. To study the effect of ER on skeletal muscle phenotype and the influence of vitamin D, rats (n = 34) were fed a control diet or an ER diet. Muscle mass, muscle somatic index (MSI), fiber-type composition, fiber size, and metabolic activity were studied in tibialis cranialis (TC) and soleus (SOL) muscles. Plasma vitamin D metabolites and renal expression of enzymes involved in vitamin D metabolism were measured. In the ER group, muscle weight was unchanged in TC and decreased by 12% in SOL, but MSI increased in both muscles (p < 0.0001) by 55% and 36%, respectively. Histomorphometric studies showed 14% increase in the percentage of type IIA fibers and 13% reduction in type IIX fibers in TC of ER rats. Decreased size of type I fibers and reduced oxidative activity was identified in SOL of ER rats. An increase in plasma 1,25(OH)₂-vitamin D (169.7 ± 6.8 vs. 85.4 ± 11.5 pg/mL, p < 0.0001) with kidney up-regulation of CYP27b1 and down-regulation of CYP24a1 was observed in ER rats. Plasma vitamin D correlated with MSI in both muscles (p < 0.001), with the percentages of type IIA and type IIX fibers in TC and with the oxidative profile in SOL. In conclusion, ER preserves skeletal muscle mass, improves contractile phenotype in phasic muscles (TC), and reduces energy expenditure in antigravity muscles (SOL). These beneficial effects are closely related to the increases in vitamin D secondary to ER.     

Utilidad de la quimioterapia neoadyuvante en el carcinoma vesical músculo invasivo no metastásico

ObjectiveWe analyzed the profile of patients who were candidates for neoadjuvant chemotherapy (NACT) in stage pT2-4aN0M0, the tolerability and adherence of our cisplatin-based protocol and oncological outcomes.Material and methodsRetrospective observational cohort study including patients diagnosed with muscle-invasive bladder carcinoma treated with NACT. Clinical, histopathological, therapeutic and evolutionary characteristics of the patients were analyzed. The use of NACT was evaluated by the complete response in the surgical specimen (pT0). This and other pathological factors were related to overall survival and progression-free survival.ResultsWe included 90 patients with muscle-invasive bladder carcinoma (clinical stage T2a-T4aN0M0) who received a cisplatin-based NACT regimen between January 2011 and December 2018, prior to radical surgery. Forty percent of patients presented an adverse reaction, with a compliance with the NACT regimen of 92.2%. There were no deaths related to systemic treatment and no adverse reaction to treatment made radical cystectomy impracticable. After performing radical cystectomy, the presence of complete response (pT0) was observed in 20 patients (21%), lower stage in the surgical specimen (<pT2) in 36 patients (40%), positive surgical margins in 7 patients (8%), lymph node involvement (N1) in 16 patients (17.8%). A shorter time to progression was observed in the group of patients who did not achieve a complete pathological response (53 months vs. 83.1 in pT0 patients, P = 0.012), in patients with lymph node involvement compared to pN0 (65.4 vs. 28, 2 months, P = 0.014) and in those with positive surgical margins compared to those with tumor-free margins (63.5 vs. 8.5 months, P = 0.021).ConclusionThe adequate selection of patients with muscle-invasive bladder carcinoma has shown a good tolerance to NACT, with a high compliance rate prior to RC. The improvement in the complete response rate implies a greater survival in this group of patients, with lymph node involvement and positive surgical margins being important prognostic factors.     

Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat

Abstract   Tumor necrosis factor alpha (TNF) injected into the sciatic nerve and neutralizing antibodies to its receptor injected around the nerve are respectively associated with inducing and blocking pain behavior beginning 1 to 3 days post-injection. This study examined the acute effects of TNF applied around the nerve trunk on the mechanical threshold (determined with von Frey hairs) and withdrawal latency to radiant heat. TNF (0.9 and 7.7 ng in 90 μL) injected onto the nerve via an indwelling catheter elicited a decrease in mechanical threshold. Following the low dose of TNF, no change in thermal latency was observed; after the 7.7 ng dose, thermal thresholds decreased and returned to baseline multiple times within the 3-hour observation period. Identical doses of TNF injected near, but not on the nerve, 90 ng of TNF injected on the nerve, and vehicle were without effect on either modality. These data indicate that effects of acutely administered TNF to the nerve trunk are capable of producing modality specific pain behavior. These changes may represent a first step in TNF-induced neuropathic pain.     

Establishment of a formal program for retinoblastoma: Feasibility of clinical coordination across borders and impact on outcome

Retinoblastoma is an ocular tumor that occurs in young children, in either heritable or sporadic manner. The relative rarity of retinoblastoma, and the need for expensive equipment, anesthesia, and pediatric ophthalmologic expertise, are barriers for effective treatment in developing countries. Also, with an average age‐adjusted incidence of two to five cases per million children, patient number limits development of local expertise in countries with small populations. Lebanon is a small country with a population of approximately 4.5 million. In 2012, a comprehensive retinoblastoma program was formalized at the Children's Cancer Institute (CCI) at the American University of Beirut Medical Center, and resources were allocated for efficient interdisciplinary coordination to attract patients from neighboring countries such as Syria and Iraq, where such specialized therapy is also lacking. Through this program, care was coordinated across hospitals and borders such that patients would receive scheduled chemotherapy at their institution, and monthly retinal examinations and focal laser therapy at the CCI in Lebanon. Our results show the feasibility of successful collaboration across borders, with excellent patient and physician adherence to treatment plans. This was accompanied by an increase in patient referrals, which enables continued expertise development. However, the majority of patients presented with advanced intraocular disease, necessitating enucleation in 90% of eyes in unilateral cases, and more than 50% of eyes in bilateral cases. Future efforts need to focus on expanding the program that reaches to additional hospitals in both countries, and promoting early diagnosis, for further improvement of globe salvage rates.