Low anterior resection syndrome (LARS): cause and effect and reconstructive considerations.

Between 25 and 80% of patients undergoing a low or very low anterior resection will suffer postoperatively, from a constellation of symptoms including fecal urgency, frequent bowel movements, bowel fragmentation and incontinence, collectively referred to as the low anterior resection syndrome (LARS). The etiology of LARS is multifactorial with the potential of sphincter injury during anastomosis construction, alterations in anorectal physiology, the development of a pudendal neuropathy, and a lumbar plexopathy with exacerbation of symptoms if there is associated anastomotic sepsis or the use of adjuvant and neoadjuavnt therapies. The symptoms of LARS may be obviated in part by the construction of a neorectal reservoir which may take the form of a colonic J-pouch, a transverse coloplasty, or a side-to-end anastomosis. This review outlines the factors contributing to LARS symptomatology along with the short- and medium-term functional results of comparative trials with the different types of neorectal reconstructions.

Mortality predictors in hospitalized elderly patients.

AIM: To find out which of the two predictors, Charlson co-morbidity index or vitamin B12, better estimates the risk of in-hospital mortality in seriously ill patients. METHOD: Electronic hospital records of 1509 elderly patients aged 65 and older were retrospectively surveyed. RESULTS: Albumin, age and elevated vitamin B12 levels were significantly associated with increased in-hospital mortality. Charlson co-morbidity index was not significantly associated with death. The highest mortality (24.3%) was found in the group of patients who were concomitantly in the lowest albumin quartile and the highest vitamin B12 levels quartile. In this group, mortality increased significantly with age. By elasticity calculation, vitamin B12 capability to predict mortality was higher by ≈ 3 times than that of Charlson co-morbidity index. CONCLUSION: In view of the fact that vitamin B12 levels have been found to predict mortality, they should be measured in geriatric practice, in addition to albumin levels, as a practical and reliable tool for identifying high risk elderly hospitalized patients. Probably, a combination of two or more available and inexpensive routinely taken tests can give a better estimation of mortality than some complicated tools, like Charlson co-morbidity index.

Power-dependent switching of nonlinear trapping by local photonic potentials.

We study experimentally and numerically the nonlinear scattering of wave packets by local multisite guiding centers embedded in a continuous dielectric medium as a function of the input power and angle of incidence. The extent of trapping into the linear modes of different sites is manipulated as a function of both the input power and the angle of incidence, demonstrating power-controlled switching of nonlinear trapping by local photonic potentials.

Interleukin-1 signaling modulates stress-induced analgesia.

Exposure to stressful stimuli is often accompanied by reduced pain sensitivity, termed "stress-induced analgesia" (SIA). In the present study, the hypothesis that interleukin-1 (IL-1) may play a modulatory role in SIA was examined. Two genetic mouse models impaired in IL-1-signaling and their wild-type (WT) controls were employed. Another group of C57 mice was acutely administered with IL-1 receptor antagonist (IL-1ra). Mice were exposed to 2min swim stress at one of three water temperatures: 32 degrees C (mild stress), 20-23 degrees C (moderate stress), or 15 degrees C (severe stress); and then tested for pain sensitivity using the hot-plate test. Corticosterone levels were assessed in separate groups of WT and mutant mice following exposure to the three types of stress. Mild stress induced significant analgesia in the two WT strains and saline-treated mice, but not in the mutant strains or the IL-1ra-treated mice. Similarly, mild stress induced significantly elevated corticosterone levels in WT mice, and blunted corticosterone response in mutant mice. In contrast, both WT and mutant strains, as well as IL-1ra-treated mice, displayed analgesic and corticosterone responses following moderate and severe stress. Interestingly, the analgesic response to moderate stress was markedly potentiated in the mutant strains, as compared with their WT controls. The present results support our previous findings that in the absence of IL-1, stress response to mild stress is noticeably diminished. However, the analgesic response to moderate stress is markedly potentiated in mice with impaired IL-1 signaling, corroborating the anti-analgesic role of IL-1 in several pain modulatory conditions, including SIA.

Postoperative pain, morphine consumption, and genetic polymorphism of IL-1beta and IL-1 receptor antagonist.

Interleukin-1 beta (IL-1beta) and its endogenous IL-1 receptor antagonist (IL-1Ra) play an important role in inflammatory response and in pain modulation. It has recently been shown that polymorphism of the IL-1beta and IL-1Ra genes may account for variation in the production of these cytokines. The present study examined the hypothesis that polymorphism of IL-1beta and IL-1Ra genes is involved in pain sensitivity and morphine consumption in the immediate postoperative period. Genetic polymorphism was determined in 76 women undergoing transabdominal hysterectomy. The genotype of IL-1Ra was determined using PCR amplification of the variable number of tandem repeats (VNTR) of 86 base pair (bp) in intron 2, while for IL-1beta the cytosine to thymine transition at codon -511 of the promoter was determined by PCR. Morphine consumption and pain scores were evaluated in the first postoperative 24 h. The study group was divided based on morphine consumption to three sub-groups: low morphine consumers (LMC) (<28 mg/24 h), medium morphine consumers (MMC) (28-38 mg/24 h), and high morphine consumers (HMC) (>38 mg/24 h). Patients consuming the least amount of morphine postoperatively showed significant lower pain scores. IL-1Ra genetic polymorphism of the MMC group was significantly different compared to the other two groups. No difference in IL-1beta gene polymorphism was found among the three sub-groups. Since IL-1Ra polymorphism is known to affect the levels of both IL-1Ra and IL-1, cytokines associated with modulation of pain sensitivity and morphine analgesia, it is suggested that IL-1Ra genetic polymorphism may contribute to the variation in postoperative morphine consumption.

Stress and pain responses in rats lacking CCK1 receptors.

UNLABELLED: CCK involvement in stress- and pain-responsiveness was examined by studying the behavior of infant (11-12-days-old) and adult OLETF rats that do not express CCK1 receptors. Infant odor- and texture-preferences were also assessed. We hypothesized that OLETF rats will show behavioral patterns similar to those previously observed after CCK1 antagonist administration. Rate of separation-induced ultrasonic vocalization was significantly greater in OLETF compared to controls, in two separate studies. Infant pups of the two strains did not differ in odor- and texture-preference tests. OLETF rats showed consistently longer hot-plate paw-lift (as infants, in two separate studies) and paw-lick (as adults) latencies. SUMMARY: OLETF pups vocalized in isolation more than controls and showed relative hypoalgesic responses, evident also in adulthood, in concordance with the pharmacological literature.

Continuous physostigmine combined with morphine-based patient-controlled analgesia in the postoperative period.

BACKGROUND: Recently, new drugs and techniques for the treatment of postoperative pain were introduced, with the goal of enhancing opiates' analgesia while minimizing their side-effects. Cholinergic agents play an antinociceptive role, but their clinical use is quite limited, due to side-effects. Physostigmine is a cholinesterase inhibitor, which crosses the blood-brain barrier and elevates brain acetylcholine level. Physostigmine can produce analgesia by itself, and enhance opiate analgesia; but these effects are of short duration following bolus administration. METHODS: We compared pain intensity and morphine consumption in two postoperative treatment groups: One group received continuous physostigmine infusion combined with morphine-based patient-controlled analgesia (PCA), and the other received PCA alone. Cholinergic anti-inflammatory pathways have recently been described. We therefore also compared changes in proinflammatory cytokine production in the two pain management groups. RESULTS: Continuous infusion of physostigmine combined with morphine-based PCA in the postoperative period significantly reduced opiate consumption, and enhanced the analgesic response. Patients in the physostigmine group also exhibited reduced ex-vivo production of the proinflammatory cytokine, IL-1beta. At the same time, physostigmine increased nausea and vomiting, mostly in the first 2 h of the postoperative period. CONCLUSIONS: Physostigmine combined with morphine in the postoperative period reduced morphine consumption, enhanced analgesia, and attenuated production of the proinflammatory cytokine, IL-1beta. This latter finding may account for the decreased pain observed in this group; this cytokine is known to mediate basal pain sensitivity and induce hyperalgesia in inflammatory conditions. Taking into account the other potential beneficial effects of physostigmine, we suggest that a continuous infusion of physostigmine should be considered as a useful component in multimodal postoperative analgesia.

Age related change of optokinetic nystagmus in healthy subjects: a study from infancy to senescence.

BACKGROUND: Optokinetic nystagmus (OKN) gain is asymmetrical between temporal to nasal (TN) and nasal to temporal (NT) stimulation in infancy and decreases at older ages. The age at which OKN gain becomes symmetrical and decreases is debated. The aim was to investigate OKN over the whole lifespan in a large sample of healthy subjects. METHODS: In a prospective, cross sectional study OKN was tested monocularly using TN and NT small field stimulation. Stimulation velocity was 15 degrees /s and 30 degrees /s for children aged under 1 year (n = 97), and 15 degrees /s, 30 degrees /s, 45 degrees /s, and 60 degrees /s for older subjects (1-9 years, n = 66; 10-89 years, n = 86). Gain was measured using infrared oculography. RESULTS: Significant OKN gain asymmetry in favour of TN versus NT stimulation was found during the first 5 months of life (p<0.05). Only at 11 months of age was OKN symmetrical in 100% of the subjects. The percentage of children with symmetrical OKN decreased with increasing stimulus velocity. OKN gain increased in the second and third years (p<0.05 for 15 degrees /s), remained stable until 50 years of age, and showed a small but significant decrease afterwards for the tested velocities (between 6% and 18%, p<0.05). CONCLUSIONS: Infrared oculography is an accurate method to assess OKN, especially in children. Knowledge about change of OKN in healthy subjects could be helpful to interpret OKN in patients with abnormal binocular vision or lesions of the central nervous system.

Illness, cytokines, and depression.

Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS-induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-alpha mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.

Epilepsia partialis continua: a new manifestation of anti-Hu-associated paraneoplastic encephalomyelitis.

We report on 3 anti-Hu-positive patients who presented with clinical and electroencephalographic (EEG) features of epilepsia partialis continua (EPC). Two of the patients had an associated small cell carcinoma. Magnetic resonance imaging (MRI) disclosed a hyperintense nonenhancing focal lesion in T2-weighted images in the sensorimotor area in 2 patients. Histopathological analysis of the lesion revealed inflammatory infiltrates and neuronal cell loss. In the patient who had a postmortem study, these neuropathological changes were not observed in other areas of the nervous system. This study emphasizes that the possibility of an anti-Hu-associated paraneoplastic disorder must be considered in patients with cortical encephalitis presenting with EPC when a brain tumor can be excluded.

Effects of mild perioperative hypothermia on cellular immune responses.

BACKGROUND: Unintentional perioperative hypothermia is a common complication of anesthesia and surgery associated with adverse effects on several systems, including impaired wound healing and more frequent wound infections. Mild hypothermia affects various immune functions. In the current study, the authors sought to determine whether immune alterations in the perioperative period might be induced, at least in part, by impaired thermoregulation during this period. METHODS: Sixty patients undergoing abdominal surgery were randomly assigned to two thermal care groups: routine care or forced-air warming. The patients' anesthetic care was standardized. Venous blood samples were collected 90 min before induction of anesthesia and immediately, 24 h, and 48 h after surgery. White cells were separated and frozen. Peripheral blood mononuclear cells were used to test cytokine production (interleukins [IL] -1beta, -2, and -6; tumor necrosis factor-alpha [TNF-alpha]), mitogens-induced proliferation, and natural killer NK cell cytotoxicity. Plasma cortisol levels were also determined. RESULTS: Patients in the normothermia group maintained normal body core temperature, whereas temperature decreased by approximately 1 degree C in the hypothermia group. Mitogenic responses were suppressed in cells from patients in the hypothermia but not in the normothermia group 24 and 48 h after surgery. Proinflammatory cytokine (IL-1beta, IL-6, TNF-alpha) production increased in both groups, although the production of IL-1beta was significantly higher in the normothermia group 24 h after surgery. Production of IL-2 was suppressed in the hypothermia but not in the normothermia group at 24 h. CONCLUSIONS: Mild perioperative hypothermia suppressed mitogen-induced activation of lymphocytes and reduced the production of certain cytokines, IL-1beta and IL-2, and in this way may contribute to the immune alterations observed in the perioperative period.

Effects of prenatal morphine exposure on NK cytotoxicity and responsiveness to LPS in rats.

Prenatal exposure to opiates can adversely affect fetal development, resulting in long-term growth retardation and impairments in physiological and behavioral functions. In the present study we studied long-term effects of prenatal morphine exposure on immune functions, including the activity of natural killer (NK) cells and the febrile and behavioral responses to lipopolysaccharide (LPS). Pregnant Fischer 344 rats were given increasing doses of morphine in slow release emulsion during gestational days 12-18. Control rats were injected with vehicle and were either pair fed to morphine rats or fed ad lib. Postnatal experiments were conducted when offspring were 10-12 weeks old. Compared to both control groups, rats prenatally exposed to morphine exhibited: 1) suppressed cytotoxic activity of NK cells; 2) reduced LPS-induced fever measured by a biotelemetric system; 3) reduced hyperalgesia measured by the hot-plate test at 30 min, and augmented hypoalgesia at 2-6 h post-LPS; 4) higher open-field activity in saline-treated animals, and more pronounced suppression of activity in LPS-injected animals; 5) LPS-induced reduction of food consumption, body weight, and social exploration, which did not differ from the reduction observed in control animals. These findings indicate that prenatal exposure to morphine induces long-term impairment of host-defense mechanisms, which may render the offspring more susceptible to infectious diseases.

Prenatal exposure to morphine feminizes male sexual behavior in the adult rat.

The endogenous opiate system plays a role in fetal sexual differentiation during development. We examined long-term effects of prenatal morphine on adult sexual behavior in male rats. Pregnant Fischer 344 rats were given increasing doses of morphine (0.75-12.0 mg/day) in slow-release emulsion during gestational days 12-18. Control rats were injected with vehicle and were either pair-fed with morphine rats or ad lib fed. At birth, all litters were culled to eight pups and fostered to naive dams. Testing began when rats were 10-12 weeks old. Masculine behavior was assessed using receptive stimulus females and recording instances of mount, intromission, and ejaculation. Feminine receptivity of the male rats was assessed following castration and priming with ovarian hormones; lordosis quotient of the experimental males was recorded using stimulus male studs. Males prenatally exposed to morphine exhibited normal rates of male copulatory behavior but a significantly higher lordosis quotient, suggesting that prenatal morphine induced long-lasting feminizing effects.

Prenatal morphine enhances morphine-conditioned place preference in adult rats.

Conditioned place preference (CPP) is a commonly used method for assessing the rewarding qualities of drugs, including opiates. In the present study, we examined long-term effects of prenatal morphine on morphine-associated place preference. Pregnant Fischer 344 rats were given increasing doses of morphine (0.75-12.0 mg/day) in slow-release emulsion during gestational days 12-18. Control rats were injected with vehicle and were fed either with morphine rats or ad libitum. At birth, all litters were culled to 8 pups and fostered to naive dams. Testing began when rats were 10-12 weeks old. Rats prenatally exposed to morphine exhibited a significantly higher preference for the morphine-paired compartment, suggesting that prenatal morphine induces a long-lasting enhancement of its reinforcing effect. Thus, prenatal morphine may result in enhanced activity and/or sensitivity of the endogenous opiate system, thereby placing the organism at higher risk for opiate drug abuse.

Prenatal exposure to morphine alters analgesic responses and preference for sweet solutions in adult rats.

In the present study, we examined long-term effects of prenatal morphine on pain response and on preference for sweet solutions. Pregnant Fischer 344 rats were given increasing doses of morphine (0.75-12.0 mg/day) in slow-release emulsion, during gestational days 12-18. Control rats were injected with vehicle and were either pair-fed to morphine rats, or ad libitum fed. At birth, all litters were culled to 8-10 pups (half males and half females) and cross-fostered to naive, surrogate dams. Testing began when rats were 10-12 week old. Rats prenatally exposed to morphine exhibited higher analgesia in response to a morphine challenge, and a greater preference for saccharin solution as compared with both control groups. These findings indicate that prenatal morphine induces long-lasting alterations of systems involved in reward processes and in opiate analgesia, perhaps by modulating endogenous opiate systems.

Prenatal naltrexone facilitates male sexual behavior in the rat.

The involvement of endogenous opiates in the differentiation of sexual behavior was tested by exposing rat fetuses to continuous naltrexone during the last 9 days of gestation. Time-mated female rats received oral naltrexone, 40 mg/kg/day, via their drinking water, from gestational day 13 until parturition. Early motor development, measured by swimming ability in 7-, 9-, and 11-day-old offspring of the treated dams, was unaffected by prenatal naltrexone. Adult male offspring were given three tests of male sexual behavior, then castrated, primed with ovarian hormones, and given two tests of feminine receptivity (lordosis quotient). Prenatal naltrexone facilitated masculine behavior and suppressed feminine receptivity: latencies to first mount and to ejaculation were shorter, mount rate was higher, and lordosis quotient was lower in naltrexone-treated rats, compared with control animals. These findings implicate endogenous opiates in prenatal organization of sex-specific behavioral dispositions.

Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period.

Surgical stress and general anesthesia suppress immune functions, including natural killer cell cytotoxicity (NKCC). This suppression could be attributable, at least in part, to opiates. We have previously shown that large-dose fentanyl administration suppressed NKCC in rats. The present study sought to compare the effects of two anesthetic protocols, based on large- (LDFA) versus small (SDFA)-dose fentanyl anesthesia on NKCC in the perioperative period. Forty patients were included in this study; half were assigned to each protocol of anesthesia. In each anesthetic group, half the patients were undergoing surgery for malignant diseases, and half for benign conditions. Blood samples were collected during the perioperative period. NKCC was assessed using the chromium release assay. Initially, both types of anesthesia similarly suppressed NKCC, with a peak effect 24 h after surgery. The two types of anesthesia, however, differed in the rate of recovery of NKCC suppression. By the second postoperative day, NKCC returned to control values in the SDFA patients, whereas NKCC was still significantly suppressed after LDFA. These results indicate that LDFA causes prolonged suppression of NK cell function. Whether this suppression might have a long-term impact on the overall outcome, especially in cancer patients, remains to be determined.

Corticosterone modulates behavioral and metabolic effects of lipopolysaccharide.

The behavioral and neuroendocrine responses following infection are important mechanisms for maintaining homeostasis and promoting recovery. The purpose of this study was to determine if glucocorticoids modulate the behavioral and metabolic effects of lipopolysaccharide (LPS) in rats. A single injection of LPS (10 micrograms/kg ip) increased plasma corticosterone at 4 h, but had no effect on social behavior, body temperature, or body weight. To determine if behavioral and metabolic effects of LPS were precluded by the increase in corticosterone, adrenalectomized (ADX) and sham-operated rats were injected with LPS. Whereas ADX rats expressed symptoms of sickness, intact controls did not. To verify that corticosterone was the adrenal hormone responsible for inhibiting these effects of LPS, corticosterone pellets or placebos were implanted intraperitoneally in ADX rats. Following injection of LPS, ADX rats with placebos expressed behavioral symptoms characteristic of sickness, including depressed social behavior. Corticosterone pellets, however, entirely reversed these effects in ADX rats. These results indicate that corticosterone modulates the behavioral and metabolic effects of LPS, suggesting that the hypothalamic-pituitary-adrenal axis is important in preventing profound behavioral disturbances in response to low-grade immune stimulation by infectious and noninfectious agents.

Age at marriage, sex-ratios, and ethnic heterogamy.

"This paper focuses on the effects of age at marriage and the sex-ratio on patterns of ethnic homogamy among Israeli women. We hypothesize that later marriages are more likely than early marriages to be heterogamous as the 'marriage market' shifts from school to the work-place. By the same token, when facing severe marriage squeezes women will be forced to out-marry. Employing data from the 1983 census, we model mate selection of women from Afro-Asian and Euro-American origin in various birth-cohorts. The results do not fully support our hypotheses: we find that in and of itself, age at marriage does not enhance ethnic heterogamy."