Integrative physiological assessment of cerebral hemodynamics and metabolism in acute ischemic stroke

Restoring perfusion to ischemic tissue is the primary goal of acute ischemic stroke care, yet only a small portion of patients receive reperfusion treatment. Since blood pressure (BP) is an important determinant of cerebral perfusion, effective BP management could facilitate reperfusion. But how BP should be managed in very early phase of ischemic stroke remains a contentious issue, due to the lack of clear evidence. Given the complex relationship between BP and cerebral blood flow (CBF)—termed cerebral autoregulation (CA)—bedside monitoring of cerebral perfusion and oxygenation could help guide BP management, thereby improve stroke patient outcome. The aim of INFOMATAS is to ‘identify novel therapeutic targets for treatment and management in acute ischemic stroke’. In this review, we identify novel physiological parameters which could be used to guide BP management in acute stroke, and explore methodologies for monitoring them at the bedside. We outline the challenges in translating these potential prognostic markers into clinical use.     

Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats

We have previously shown in rats that the provision of analgesic doses of morphine significantly reduces the tumor-promoting effects of undergoing and recovering from surgery. Because morphine had no effect in non-operated animals, and because a single preoperative dose given hours before tumor inoculation was effective, we have suggested that it is the pain-relieving effects of the drug that underlies its beneficial impact. To support and strengthen this suggestion, two different regimens of analgesia were employed, the systemic administration of the more selective mu-agonist, fentanyl, and the intrathecal (i.t.) administration of bupivacaine plus morphine. To assess host resistance against metastasis, we used a lung clearance assay of the MADB106 mammary adenocarcinoma, a natural killer (NK)-sensitive syngeneic cell line that metastasizes only to the lungs. Female and male Fischer 344 rats were randomly assigned to one of four groups using a 2x2 experimental design: experimental laparotomy under halothane anesthesia versus anesthesia alone, by drug treatment versus vehicle. In the first in vivo experiment, fentanyl was administered 20 min before surgery (40 microg/kg subcutaneously (s.c.)), and at the end of surgery in a slow-release suspension (20 microg/kg s.c.). In the second in vivo experiment, bupivacaine (10 microg) plus morphine (20 microg) in 50 microl was administered i.t. before surgery. Surgery resulted in a 3- to 4-fold increase in the lung retention of MADB106 cells in both males and females, and the observed surgery-induced increase in lung tumor retention was reduced by more than 65% in the fentanyl-treated animals and more than 45% in the animals receiving i.t. bupivacaine plus morphine. Neither drug regimen exerted effects in the anesthesia only animals. Surgery also resulted in a significant suppression of whole blood NK activity assessed at 5 h postoperatively, the same time point at which MADB106 tumor cells were inoculated in the in vivo studies. Unlike the in vivo study, fentanyl suppressed NK activity at this time point in non-operated rats, but had no effect in operated rats. Taken together, these findings strengthen the suggestion that the management of perioperative pain is a critical factor in preventing surgery-induced decreases in host resistance against metastasis. If similar relationships between pain and metastasis occur in humans, then pain control must become a priority in the postoperative care of individuals with cancer.     

CHANGES IN THE PLASMA PROTEIN PATTERN (TISELIUS ELECTROPHORETIC TECHNIC) OF PATIENTS WITH HYPERTENSION AND DOGS WITH EXPERIMENTAL RENAL HYPERTENSION

The plasma protein pattern of patients with uncomplicated essential hypertension showed only slight variations from the normal while that of patients with severely malignant hypertension showed marked shifts. The fibrinogen and β-globulins were usually elevated beyond the normal range and the albumin decreased. In less severely malignant hypertension, the changes were less marked. In dogs with experimental renal hypertension, the γ-globulin level was greatly elevated, and in one animal exhibiting the malignant syndrome β-globulin and fibrinogen were also increased. Elevation of β-globulin seems in some manner associated with the occurrence of severe vascular disease.     

THE REACTION OF PERIPHERAL BLOOD VESSELS TO ANGIOTONIN,RENIN, AND OTHER PRESSOR AGENTS

1. Both renin and angiotonin in small doses cause constriction of the arterioles in the ears of normal rabbits, as seen directly with the microscope. Capillaries appear unaffected while venules exhibit slight or no constriction with small doses and moderate constriction with large doses. The flow of blood through the tissues is not reduced except when very large doses are administered. Tyramine and methylguanidine sulfate in isopressor amounts act somewhat similarly. 2. Isopressor amounts of epinephrine and pitressin, by contrast, elicit severe vasoconstriction of arterioles lasting longer than that due to angiotonin, and flow of blood is sharply reduced or abolished altogether. The degree of venular constriction was also greater, while the capillaries remained unaffected. 3. The vasoconstrictor action of angiotonin on peripheral vessels in moat chambers in normal rabbit''s ears is indistinguishable from that of renin, except that it is more rapid.     

Facial-Skin Hyperpigmentation： Histological and Computer Geometric Assessment

Hyper-pigmentation is a common, acquired dermatological skin-disorder manifesting and identifiable as irregular brown or greyish-brown facial discolouration, and sometimes referred to as melanosis, melasma or hypermelanosis. Purpose and Objective： To identify the site of melanin deposition in skin-layers regarding facial hyper-pigmentation, based on a histological study of full-thickness skin-facial biopsies in aged Caucasian-cadavers. Hypothesis： Recalcitrant hyper-pigmentation, is chiefly characterised by hyper-melanosis restricted to the dermal-layer of the integument. Method： The histological features of facial hyper-pigmentation and solar-lentigenes were evaluated in a pilot-study of 5-randomly selected Caucasian-cadavers with pigmentation （15 facial biopsies）, ranging in age between 75 and 102 years （mean 77-years）. Selection-criteria included, both genders, age 〉 75, focal and confluent hyper-pigmented lesions, involving sun-exposed areas of skin （centrifacial, scalp, malar, mandibular and cervical）. Study groups included （Grp-1： Control skin-histology in otherwise normal aged, human-cadavers; Grp-2： Histology of pigmented facial skin-lesions in man; Grp-3： Comparative histological skin-controls in non-human primates）. No obvious hepatic disease was evident in the cohort studied. Twenty-five histological controls were obtained from non-pigmented areas. Histological evaluation of full-thickness skin-biopsies （including the lesion, edge and peri-]esion skin）, was under a Leitz~-light-microscope, and staining included H＆E, Masson-trichrome, Masson-fontana, Alcian-blue and Verhoef technology. Histological-scoring used was on histological deposition of melanin in skin-layers： epidermal, dermal, mixed, and indeterminate melanin-deposition （score 1-4）. Controls included cadaveric skin-biopsies of human races of colour and non-human primate, Cercopethicus Aethiops （latter is known to have predominantly dermal-melanin deposition）. Pigmented and non-pigmented areas were compared in both species. Results： The majority of clinically visible individual and confluent areas of hyper-pigmentation studied were maeroscopically present on the forehead, frontal scalp in hair-receded cadavers, molar and temporal zones. Histologically, documented features of age-related changes without pigment were present in almost all the embalmed cadaver-skins, with a melanin-score of 1. Computer enhanced skin geometry and biometrics confirmed the presence of an aged-skin, pigmentation and features of solar damage. The human embalmed-tissue was well preserved and minimal autolytic changes were present. Special stains of full-thickness biopsies （Masson-Fontana）, showed that melanin in the subhuman-primate is lodged in the deep dermis （reticular dermis）, within the extra-cellular matrix （ECM） and superficial to the hypodermal adipose-tissue （melanin-score 3）. Fifteen pigmented lesions studied in five （5） aged-cadavers （forehead, molar and mandibular areas） all showed predominantly epidermal-deposition of melanin in the basal, suprabasal and stratum corneum with tiny focal areas of dermal melanosis in single-cell macrophages in the papillary-dermis but not reticular-dermis （melanin-score 2）. A melanin-deposition localization ratio of epidermis to dermis was approximately 98 to 2% in cadavers with hyper-pigmentation. Conclusion： The skin-strata localization of the melanin with regards hyper-pigmentation of the face and forehead in this aged, human adult Caucasian, cadaveric-study, was predominantly in the epidermis and sparse in the papillary dermis.     

Prostaglandin E<Subscript>2</Subscript> Suppresses NK Activity In Vivo and Promotes Postoperative Tumor Metastasis in Rats

Background: Prostaglandins (PGs) were shown in vitro to suppress several functions of cellular immunity. It is unclear, however, whether physiological levels of PGs can suppress cellular immunity in vivo and whether such suppression would compromise postoperative host resistance to metastasis.Methods: Fischer 344 rats were administered PGE₂ in doses (18 to 300 g/kg subcutaneously) that increased the serum levels approximately 2- to 4-fold. We then assessed the number and activity of circulating natural killer (NK) cells, as well as rats resistance to experimental metastasis of a syngeneic NK-sensitive tumor (MADB106). To study whether endogenously released PGs after surgery compromise these indices, we tested whether laparotomy adversely affects them and whether a cyclooxygenase-synthesis inhibitor, indomethacin (4 mg/kg), attenuates these effects.Results: PGE₂ dose-dependently suppressed NK activity per NK cell and dose-dependently increased 4- and 24-hour MADB106 lung tumor retention (LTR); 240 g/kg of PGE₂ quadrupled the number of lung metastases counted 3 weeks later. Selective depletion of NK cells abrogated the promotion of LTR by PGE₂. Surgery significantly suppressed NK activity and increased MADB106 LTR, and indomethacin halved these effects without affecting nonoperated rats.Conclusions:PGE₂ is a potent in vivo suppressor of NK activity, and its postoperative release may promote tumor recurrence.