Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.     

Neurocognitive functioning among people accessing an addiction neuropsychology clinic with and without a history of offending behaviour

Effectiveness of interventions for violent behaviour may be undermined by the presence of neurocognitive impairment, which is known to be common among alcohol and other drug (AOD) users and violent offenders. The current study aimed to examine whether the cognitive functioning of individuals with AOD histories presenting to a specialist addiction neuropsychology service differed according to their offending history (i.e. non-offending, non-violent offending and violent offending), using a retrospective case file audit design. Data were extracted from 190 clients. Tests assessed a breadth of cognitive domains. Violent offenders demonstrated the lowest premorbid IQ out of the three groups, and a significantly higher proportion of violent offenders presented with impaired divided attention and impaired cognitive inhibition compared to non-violent offenders. Rates of impairment across groups were well beyond those expected within the general population. Delivery of both AOD and violence interventions should be adapted to accommodate individuals’ cognitive difficulties.Key words: alcohol and drug use, cognitive functioning, cognitive impairment, intervention, neurocognitive impairment, neuropsychology, offender, rehabilitation, treatment, violence

The number of people in prisons in Australia has increased by 25% between 2013 and 2018 (Australian Bureau of Statistics, 2019b), which is 2.6 times greater than the increase in the Australian population over that same period (9.6%; Australian Bureau of Statistics, 2019a). Of the prisoners released during 2015–2016, 43.7% returned to prison within two years (Justice & Regulation, 2018). This high rate of recidivism is despite the availability of programmes and psychological interventions during incarceration, community corrections orders or parole, and include those addressing alcohol and other drug (AOD) use and offending behaviour (Heseltine et al., 2011). However, the prevalence of AOD use remains a significant issue for the criminal justice system (Casey & Day, 2014), and is often associated with violent offending (Voce & Sullivan, 2019). For example, in 2018, 79% of police detainees across Australia who produced a positive urinalysis for drugs had committed a violent offence, and almost half of the sample (43%) attributed their violent offending to their AOD use (particularly alcohol and methamphetamine; Voce & Sullivan, 2019), which is consistent with international data (Bahr et al., 2012).AOD use and violent behaviour have been consistently associated with neurocognitive impairment (Boles & Miotto, 2003; Cadet & Bisagno, 2015; Crowe et al., 2020; Potvin et al., 2018; Potvin et al., 2014; Stavro et al., 2013). Neurocognitive impairment is an important factor to consider when selecting appropriate behaviour change interventions as it can affect people’s ability to make changes, and may limit engagement in, and response to, intervention (Rupp et al., 2012). Specifically, violent offenders have been found to have specific impairments in inhibitory control, emotional processing and divided attention (Bell & Polaschek, 2017; Bergvall et al., 2001; Yang & Raine, 2009), as well as more broad patterns of executive dysfunction (Broomhall, 2005; Hancock et al., 2010). These are similar impairments to those experienced by individuals with AOD use disorders, which also include aspects of executive functioning such as planning, use of environmental feedback, response inhibition, working memory and goal selection, in addition to learning and memory (Bates et al., 2002; Pitel et al., 2009). These skills are necessary for a successful response to interventions commonly used for aggression/violence, such as cognitive behaviour therapy (CBT), or motivational enhancement (Blume & Marlatt, 2009; Rupp et al., 2012).Importantly, neurocognitive impairments can persist for weeks or months after the cessation of AOD use, in some cases only returning to a normal range after lengthy periods (i.e. 12 or more months) of abstinence (Stavro et al., 2013), while in other cases deficits may persist (Crowe et al., 2020; Crowe & Stranks, 2018). Furthermore, populations with AOD use disorders often present with high rates of comorbid risk factors for cognitive impairment including educational disadvantage, trauma, mental health and head injury (Gooden et al., 2020; Jackson et al., 2011; Morisano et al., 2014).Given that cognitive impairment can be present in both AOD use disorder (Bates et al., 2002, 2013) and violent offending populations (Rosell & Siever, 2015), violent offenders with severe AOD use disorders may be more vulnerable to experiencing higher rates of, or more severe, cognitive impairment. This in turn may limit their ability to access or engage in treatment programmes. Furthermore, there is a risk that these impairments may go undetected or be underestimated despite their impact on intervention outcomes (Bernardin et al., 2014). As such, characterising the nature of these impairments and determining whether individuals in this group present with differing levels of cognitive impairment is the first step in ensuring these weaknesses can be considered and treatment programmes adequately adapted.This study aimed to explore and contrast the neuropsychological performance of (a) those with no offending history, (b) those with a history of non-violent offending and (c) those with a history of violent offending, who presented to a state-wide addiction neuropsychology service in Melbourne, Victoria, Australia. Specifically, we compared both mean scores and the proportion with scores in the impaired range across three groups defined by their history of offending behaviour. Based on existing literature, we predicted that violent offenders would demonstrate poor performance on tests of executive control (inhibition, divided attention and working memory) relative to that of non-violent offenders and non-offenders. Additionally, we aimed to determine the rates at which these groups differed from the normal range on domains of cognitive functioning and explore any differences between groups.     

State of the art and recommendationsKangaroo mother care: application in a high‐tech environment

Since Kangaroo Mother Care (KMC) was developed in Colombia in the 1970s, two trends in clinical application emerged. In low income settings, the original KMC model is implemented. This consists of continuous (24 h/day, 7 days/week) and prolonged mother/parent–infant skin‐to‐skin contact; early discharge with the infant in the kangaroo position; (ideally) exclusive breastfeeding; and, adequate follow‐up. In affluent settings, intermittent KMC with sessions of one or a few hours skin‐to‐skin contact for a limited period is common. As a result of the increasing evidence of the benefits of KMC for both infants and families in all intensive care settings, KMC in a high‐tech environment was chosen as the topic for the first European Conference on KMC, and the clinical implementation of the KMC model in all types of settings was discussed at the 7th International Workshop on KMC. Kangaroo Mother Care protocols in high‐tech Neonatal Intensive Care Units (NICU) should specify criteria for initiation, kangaroo position, transfer to/from KMC, transport in kangaroo position, kangaroo nutrition, parents’ role, modification of the NICU environment, performance of care in KMC, and KMC in case of infant instability. Conclusion: Implementation of the original KMC method, with continuous skin‐to‐skin contact whenever possible, is recommended for application in high‐tech environments, although scientific evaluation should continue.     

Recovery of olfactory behavior. I. Recovery after a complete olfactory bulb lesion correlates with patterns of olfactory nerve penetration

The olfactory system is an excellent system in which to study issues related to potential functional recovery after a debilitating brain injury. The olfactory system is well-characterized, easily accessible and there are a vast number of studies available from a variety of perspectives. The experimental aim of this research is to examine the anatomical correlates associated with potential behavioral recovery in rats that receive complete olfactory bulb lesions as neonates or as adults. The results show that behavioral recovery occurs only when olfactory nerve penetration of the central nervous system is observed. Further, both olfactory nerve penetration and behavioral recovery are age-dependent phenomena. The olfactory nerve penetration only occurs when the olfactory bulb lesion is performed in neonates. Behavioral recovery of olfactory ability follows a linear trend and reaches near normal levels during the six week behavioral testing period. Histological analysis using an antibody for olfactory marker protein (an olfactory nerve-specific marker) reveals two potential candidates for the anatomical pathway responsible for behavioral recovery: olfactory nerve to orbital frontal cortex and olfactory nerve to olfactory peduncle. This report presents evidence that recovery of olfactory ability can occur in the absence of the olfactory bulb if the lesion is performed when the rat is still a neonate.     

Arthrogryposis multiplex congenita. Search for prenatal factors in 66 sporadic cases

In a family and epidemiological survey of 66 cases of arthrogryposis multiplex congenita all cases were found to be sporadic and no family association with clubfoot, congenital dislocation of the hip, or hereditary neuromuscular disease was found. The mothers were significantly older than average. Oligohydramnios was noted in only one-third of cases but many other complications of pregnancy, including probable attempts at abortion, had occurred. It is likely that most cases of arthrogryposis are nongenetic and result from a defective intrauterine environment, whether hormonal, vascular, mechanical, or possibly infective.     

A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells

Many key regulatory proteins, including members of the Ras family of GTPases, are modified at their C terminus by a process termed prenylation. This processing is initiated by the addition of an isoprenoid lipid, and the proteins are further modified by a proteolytic event and methylation of the C-terminal prenylcysteine. Although the biological consequences of prenylation have been characterized extensively, the contributions of prenylcysteine methylation to the functions of the modified proteins are not well understood. This reaction is catalyzed by the enzyme isoprenylcysteine carboxyl methyltransferase (Icmt). Recent genetic disruption studies have provided strong evidence that blocking Icmt activity has profound consequences on oncogenic transformation. Here, we report the identification of a selective small-molecule inhibitor of Icmt, 2-[5-(3-methylphenyl)-1-octyl-1H-indol-3-yl]acetamide (cysmethynil). Cysmethynil treatment results in inhibition of cell growth in an Icmt-dependent fashion, demonstrating mechanism-based activity of the compound. Treatment of cancer cells with cysmethynil results in mislocalization of Ras and impaired epidermal growth factor signaling. In a human colon cancer cell line, cysmethynil treatment blocks anchorage-independent growth, and this effect is reversed by overexpression of Icmt. These findings provide a compelling rationale for development of Icmt inhibitors as another approach to anticancer drug development.     

Parotid gland tumours in 255 consecutive patients: Mount Sinai Hospital's quality assurance review

Parotid neoplasms represent a diverse group of tumours found in the head and neck. Complications following parotidectomy, including Frey's syndrome, facial nerve paralysis, sialoceles, and parotid fistulae, have been well documented. A retrospective review of 255 patients treated surgically for parotid masses over an 8-year period at Mount Sinai Hospital in Toronto was reviewed as part of a quality assurance program. The sensitivity, specificity, and predictive values for fine-needle aspiration cytology were analyzed. The incidence of benign and malignant lesions is presented. The complications following parotidectomy are reviewed and in our series are consistent with the figures published in the literature.     

3,4-二氯苯丙烯酰另丁胺对大鼠脑缺血-再灌注损伤的影响

目的：研究新的桂皮酰胺类衍生物,３－４二氯苯丙烯酰另丁胺（ＡＥＤ８８０１）对大鼠脑缺血／再灌注损伤的影响。方法：采用Ｐｕｌｓｉｎｅｌｌｉ四血管阻断大鼠脑缺血／再灌注模型,观察了ＡＥＤ８８０１对脑组织中水含量、氨基到含量、６－ｋｅｔｏ－ＰＧＦ１α和ＴＸＢ２含量,以及二者之比值的影响。结果：一ＡＥＤ８８０１能够降低脑缺血／再灌注大鼠所引起的脑水含量增加。二采用氨基酸自动分析仪进行检测,发现脑缺血／再灌