Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies

Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100–250 mg m−2 was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m−2 day−1. Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax ~1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m−2 day−1 for 5 days, every 28 days, is recommended for phase II studies. © 1999 Cancer Research Campaig

Antipsychotic withdrawal symptoms: Phenomenology and pathophysiology

The authors review the literature discribing non-dyskinetic antipsychotic withdrawal phenomena. Withdrawal of these agents can cause nausea, emesis, anorexia, diarrhea, rhinorrhea, diaphoresis, myalgia, paresthesia, anxiety, agitation, restlessness, and insomnia. Psychotic relapse is often presaged by increased anxiety, agitation, restlessness and insomnia, but the temporal relationship of these prodromal symptoms to reduction in the dosage or discontinuation of neuroleptics distinguishes them from the effects of abrupt withdrawal.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65190/1/j.1600-0447.1988.tb05116.x.pd

Analysis of the FGF gene family provides insights into aquatic adaptation in cetaceans

Cetacean body structure and physiology exhibit dramatic adaptations to their aquatic environment. Fibroblast growth factors (FGFs) are a family of essential factors that regulate animal development and physiology; however, their role in cetacean evolution is not clearly understood. Here, we sequenced the fin whale genome and analysed FGFs from 8 cetaceans. FGF22, a hair follicle-enriched gene, exhibited pseudogenization, indicating that the function of this gene is no longer necessary in cetaceans that have lost most of their body hair. An evolutionary analysis revealed signatures of positive selection for FGF3 and FGF11, genes related to ear and tooth development and hypoxia, respectively. We found a D203G substitution in cetacean FGF9, which was predicted to affect FGF9 homodimerization, suggesting that this gene plays a role in the acquisition of rigid flippers for efficient manoeuvring. Cetaceans utilize low bone density as a buoyancy control mechanism, but the underlying genes are not known. We found that the expression of FGF23, a gene associated with reduced bone density, is greatly increased in the cetacean liver under hypoxic conditions, thus implicating FGF23 in low bone density in cetaceans. Altogether, our results provide novel insights into the roles of FGFs in cetacean adaptation to the aquatic environment.ope

Realising the right to data portability for the domestic Internet of Things

There is an increasing role for the IT design community to play in regulation of emerging IT. Article 25 of the EU General Data Protection Regulation (GDPR) 2016 puts this on a strict legal basis by establishing the need for information privacy by design and default (PbD) for personal data-driven technologies. Against this backdrop, we examine legal, commercial and technical perspectives around the newly created legal right to data portability (RTDP) in GDPR. We are motivated by a pressing need to address regulatory challenges stemming from the Internet of Things (IoT). We need to find channels to support the protection of these new legal rights for users in practice. In Part I we introduce the internet of things and information PbD in more detail. We briefly consider regulatory challenges posed by the IoT and the nature and practical challenges surrounding the regulatory response of information privacy by design. In Part II, we look in depth at the legal nature of the RTDP, determining what it requires from IT designers in practice but also limitations on the right and how it relates to IoT. In Part III we focus on technical approaches that can support the realisation of the right. We consider the state of the art in data management architectures, tools and platforms that can provide portability, increased transparency and user control over the data flows. In Part IV, we bring our perspectives together to reflect on the technical, legal and business barriers and opportunities that will shape the implementation of the RTDP in practice, and how the relationships may shape emerging IoT innovation and business models. We finish with brief conclusions about the future for the RTDP and PbD in the IoT

Symptomatic reactions, clinical outcomes and patient satisfaction associated with upper cervical chiropractic care: A prospective, multicenter, cohort study

<p>Abstract</p> <p>Background</p> <p>Observational studies have previously shown that adverse events following manipulation to the neck and/or back are relatively common, although these reactions tend to be mild in intensity and self-limiting. However, no prospective study has examined the incidence of adverse reactions following spinal adjustments using upper cervical techniques, and the impact of this care on clinical outcomes.</p> <p>Methods</p> <p>Consecutive new patients from the offices of 83 chiropractors were recruited for this practice-based study. Clinical outcome measures included 1) Neck pain disability index (100-point scale), 2) Oswestry back pain index (100-point scale), 3) 11-point numerical rating scale (NRS) for neck, headache, midback, and low back pain, 4) treatment satisfaction, and 5) Symptomatic Reactions (SR). Data were collected at baseline, and after approximately 2 weeks of care. A patient reaching sub-clinical status for pain and disability was defined as a follow-up score <3 NRS and <10%, respectively. A SR is defined as a new complaint not present at baseline or a worsening of the presenting complaint by >30% based on an 11-point numeric rating scale occurring <24 hours after any upper cervical procedure.</p> <p>Results</p> <p>A total of 1,090 patients completed the study having 4,920 (4.5 per patient) office visits requiring 2,653 (2.4 per patient) upper cervical adjustments over 17 days. Three hundred thirty- eight (31.0%) patients had SRs meeting the accepted definition. Intense SR (NRS ≥8) occurred in 56 patients (5.1%). Outcome assessments were significantly improved for neck pain and disability, headache, mid-back pain, as well as lower back pain and disability (<it>p </it><0.001) following care with a high level (mean = 9.1/10) of patient satisfaction. The 83 chiropractors administered >5 million career upper cervical adjustments without a reported incidence of serious adverse event.</p> <p>Conclusions</p> <p>Upper cervical chiropractic care may have a fairly common occurrence of mild intensity SRs short in duration (<24 hours), and rarely severe in intensity; however, outcome assessments were significantly improved with less than 3 weeks of care with a high level of patient satisfaction. Although our findings need to be confirmed in subsequent randomized studies for definitive risk-benefit assessment, the preliminary data shows that the benefits of upper cervical chiropractic care may outweigh the potential risks.</p

Chewing Through the Miocene: An Examination of the Feeding Musculature in the Ground Sloth Hapalops from South America (Mammalia: Pilosa)

Hapalops, a smaller-sized and early sloth of the Megatheroidea, appeared in the middle Miocene Santa Cruz formation of Argentina. This genus is part of the group from which later, larger megatheroids arose, i.e., Nothrotheriops and Megatherium. Many cranial characters support this idea; however Hapalops is not merely a smaller antecedent of the later forms. Specifically, Hapalops retains short anterior caniniform teeth, and a temporomandibular joint elevated above the cheek tooth row; a combination distinct among sloths. An elevated temporomandibular joint occurs in Bradypus, a tree sloth with anterior chisel-shaped teeth instead of caniniforms, and the tree sloth Choloepus, which is aligned with the megalonychids, has anterior caniniforms. Hapalops has an elongated zygomatic ascending process that is reminiscent of that in Bradypus; however, the Bradypus skull is extremely foreshortened while that of Hapalops is elongated, as in nothrotheres, but not deepened as in megatheres. Previous work identified many sloth cranial character complexes, and functional limitations on skull feature combinations. The unique Hapalops character patterns indicate a selective feeder with a mediolaterally oriented grinding stroke during mastication