Sapropterin dihydrochloride, 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin,in the treatment of phenylketonuria

Sapropterin dihydrochloride, 6-R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is being introduced in the US for treatment of phenylketonuria (PKU). This compound has been in use in Europe to treat mild forms of PKU. Tetrahydrobiopterin is the cofactor in the hydroxylation reaction of the three aromatic amino acids phenylalanine, tyrosine and tryptophan. It is also involved in other reactions, which are not the focus of this review. The cofactor BH4 is synthesized in many tissues in the body. The pathway of BH4 biosynthesis is complex, and begins with guanosine triphosphate (GTP). The first reaction that commits GTP to form pterins is GTP cyclohydrolase. Several reactions follow resulting in the active cofactor BH4. During the hydroxylation reaction BH4 is oxidized to quinonoid-BH2, which is recycled by dihydropteridine reductase, resulting in the active cofactor. It was discovered that some patients with PKU had a decline in blood phenylalanine after oral intake of BH4. This response to BH4 is not the result of change in the synthesis or regeneration of the cofactor, but rather an effect on the mutant enzyme phenylalanine hydroxylase either by accommodating the higher K_m of the mutant enzyme or by acting as a chaperone for the mutant enzyme. This response has become of intense interest in the treatment of PKU.     

唐山市苯丙酮尿症患儿筛查及PAH基因突变情况分析

摘要：目的　分析唐山市苯丙酮尿症（PKU）患儿筛查结果及苯丙氨酸羟化酶（PAH）基因突变的情况。方法　选取2015年1月—2018年12月唐山市新生儿303 777例,通过茚三酮免疫荧光法检测新生儿足跟血中苯丙氨酸（PA）含量。再利用聚合酶链反应（PCR）和基因测序的方法对筛查出的PKU患儿PAH基因进行检测。结果　303 777例新生儿初步筛查共发现609例可疑阳性,召回其中411例（67.49%）进行复查,确诊42例（13.8/10万）。42例PKU患者的PAH基因测序显示,在84条染色体上共检测到62个（73.81%）12种突变,其中错义突变8种,无义突变2种,缺失突变1种,剪接突变1种。患者PAH基因突变分布在第2、3、6、7、9外显子上,其中第7外显子最多（35个,56.45%）,其次为第3外显子（14个,22.58%）。最常见的突变基因为Exon7-R243Q（18个,29.03%）和Exon3-R111X（10个,16.13%）、Exon7-R261Q（10个,16.13%）。筛查中发现1例典型PKU患儿,该患儿在PAH基因外显子区域同时发现2处杂合突变：c.208-210delTCT（缺失突变）和c.964G＞A（鸟嘌呤＞腺嘌呤）。结论　唐山市新生儿PKU发病率略高于全国,PAH基因突变以错义突变为主,第7外显子是唐山市患儿PAH基因高频突变位点。     

Tolerance of Silene vulgaris to copper: Population‐related comparison of selected physiological parameters

Tolerance of three Slovak populations of Silene vulgaris [from the localities “Harmanec” (total soil Cu 34.1 mg kg^?1), “Lubietová”; (total soil Cu 831.6 mg kg^?1) and “?pania dolina” (total soil Cu 1368.7 mg kg^?1) referred as SV1, SV2, and SV3, respectively] and Silene dioica (SD; from the locality “?pania dolina”) exposed to 60 μM Cu for 7 days has been studied. Respective controls with 0.21 μM Cu were also cultured. SV3 and SD contained higher total shoot Cu than SV1. Methanol‐soluble shoot Cu represented 60, 59, 59, and 55% from total shoot Cu and roots contained 16.7‐, 20.4‐, 9.9‐ and 28.9‐fold more Cu than shoots in SV1, SV2, SV3, and SD, respectively. Soluble proteins were the least affected in SV3 and SD when Cu‐exposed and control plants were compared. Root hydrogen peroxide and superoxide showed similar trend and were correlated with enhancement of ascorbate‐ and guaiacol‐peroxidase activities. Malondialdehyde accumulation increased in SV1 and SV2. Phenylalanine ammonia‐lyase activity and total soluble phenols were higher in SV3 Cu‐exposed plants compared to SV1 and SV2. Shikimate dehydrogenase activity was enhanced in all Cu‐exposed populations. Cinnamyl alcohol dehydrogenase activity and root lignin content were not affected and polyphenol oxidase activity was not detected. Within 14 detected free amino acids, majority of them decreased preferentially in the roots. Only serine increased in shoots and decreased in roots of all populations. Potassium content was not affected in SV3. Na, Ca, and Fe increased in roots of Cu‐exposed plants of all populations, while Mg was the least affected and Zn increased in SV2 and SV3 shoots and roots. This study revealed the highest tolerance in population from the locality with the highest soil Cu content. Present findings as complex metabolic responses to Cu stress with special emphasis on phenolic metabolism are discussed. © 2009 Wiley Periodicals, Inc. Environ Toxicol 25: 581–592, 2010.     

Physiological responses of Matricaria chamomilla to cadmium and copper excess

Physiological responses of Matricaria chamomilla plants exposed to cadmium (Cd) and copper (Cu) excess (3, 60, and 120 microM for 7 days) with special emphasis on phenolic metabolism were studied. Cu at 120 microM reduced chamomile growth, especially in the roots where it was more abundant than Cd. Notwithstanding the low leaf Cu amount (37.5 microg g(-1) DW) in comparison with Cd (237.8 microg g(-1) DW) at 120 microM, it caused reduction of biomass accumulation, F(v)/F(m) ratio and soluble proteins. In combination with high accumulation of phenolics, strong reduction of proteins and high GPX activity in the roots, this supports severe redox Cu properties. In terms of leaf phenylalanine ammonia-lyase (PAL) activity, it seems that Cd had a stimulatory effect during the course of the experiment, whereas Cu was found to stimulate it after 7-day exposure. The opposite trend was visible in the roots, where Cd had a stimulatory effect at high doses but Cu mainly at the highest dose. This supports the assumption of different PAL time dynamics under Cd and Cu excess. A dose of 60 and 120 microM Cu led to 2- and 3-times higher root lignin accumulation while the same Cd doses increased it by 33 and 68%, respectively. A Cu dose of 120 microM can be considered as limiting for chamomile growth under conditions of present research, while resistance to high Cd doses was confirmed. However, PAL and phenolics seemed to play an important role in detoxification of Cd- and Cu-induced oxidative stress.     

Endometrial Cancer—current state of the art therapies and unmet clinical needs: The role of surgery and preoperative radiographic assessment

Endometrial carcinoma is the fourth most common cancer among women in the United States. Surgical pathologic staging has been the standard of care since 1988, which consists of analysis of collected peritoneal fluid, hysterectomy/oophorectomy, and pelvic and para-aortic lymphadenectomy. In 2005, it was further recommended that essentially all women with endometrial cancer who choose to undergo surgery have pelvic and para-aortic lymph node analysis. Despite this recommendation, there still remains controversy as to whether all patients with endometrial cancer should undergo full lymph node dissection. In this review, we assess the evidence surrounding this controversy and conclude that women with endometrial cancer should undergo complete lymphadenectomy at the time of surgery. Furthermore, we evaluate the evidence regarding laparoscopic surgical staging as a safe and effective alternative to the more invasive traditional laparotomy. Finally, for those patients who a gynecologic oncologist is not readily available to perform a complete lymph node dissection, we evaluate the various imaging studies and their utility as preoperative triage modalities.     

Functional cognitive assessment scale (FUCAS): a new scale to assess executive cognitive function in daily life activities in patients with dementia and mild cognitive impairment

BACKGROUND: Several tests have been developed to examine performance of demented patients in daily life activities. However, most of them are based either on the subjective evaluation of performance by the patient him/herself, or on the reports of relatives. Functional Cognitive Assessment Scale (FUCAS) is a new reliable (alpha > 0.89 - 0.92) cognitive-behavioral scale that assesses executive function in daily life activities directly in patients with dementia. AIMS: This study aimed at testing FUCAS' internal consistency of items, criterion-related validity, interrater reliability, discriminative ability, and effect of age, sex, and education on FUCAS scores. RESULTS: Criterion-related validity was supported by significant correlations between FUCAS, CAMCOG, MMSE, and FRSSD. The interrater reliability of FUCAS' total score for two raters was r 0.997 and we found no significant effect of age, sex, or education on FUCAS' total performance. Discriminant analysis has identified that FUCAS was able to sufficiently discriminate the patients with MCI from those with moderate-severe dementia. CONCLUSION: FUCAS is a useful and reliable diagnostic tool for MCI. Cognitive-behavioral assessment such as that provided by FUCAS can provide objective information that can serve to enhance the quality of clinical decision-making.     

Regulatory needs and activities to address the retinoid system in the context of endocrine disruption: The European viewpoint

Endocrine disruption continues to be a matter of high concern, and a subject of intensive activities at the public, political, regulatory and academic levels. Currently, available regulatory test guidelines (TGs) relevant to the identification of endocrine disrupters are largely limited to estrogen, androgen, thyroid and steroidogenesis (EATS) pathways. Thus, there is an increasing interest and need to develop test methods, biomarkers, and Adverse Outcome Pathways (AOPs), for identification and evaluation of endocrine disrupters in addition to the EATS pathways. An activity focusing on the retinoid system has been jointly initiated by the Swedish Chemicals Agency and the European Commission. The retinoid system is involved in fundamental life processes and has been described, in previous work at the OECD, as a system susceptible to environmental endocrine disruption, the disruption of which could contribute to the increasing incidence of certain disorders in humans and wildlife populations.     

The role of the new basal insulin analogs in addressing unmet clinical needs in people with type 1 and type 2 diabetes

Background: Despite improvements in anti-hyperglycemic therapies, there are many unmet clinical needs that hinder successful glycemic control in people being treated with current basal insulin analogs.

Objective: This paper reviews the unmet needs associated with current basal insulin therapy and describes the most recent basal insulins for the treatment of diabetes.

Methods: PubMed was searched for articles on basal insulin analogs published between 2000 and April 2016.

Results: Although long-acting insulin analogs, such as insulin glargine 100 units/mL and insulin detemir, have come towards approximating physiologic basal insulin levels, limitations such as hypoglycemia and intra- and inter-individual variability are associated with their use resulting in glycemic fluctuations. Some basal insulins lack 24?hour coverage, requiring some patients to split their dose, increasing the number of injections required to maintain glycemic control. Fear of hypoglycemia and the need for additional injections often leads to poor compliance and suboptimal glycemic control. Long-acting insulin analogs, such as insulin glargine 300 units/mL and insulin degludec, have improved upon the shortcomings of the current basal insulin analogs. Improved pharmacodynamic/pharmacokinetic profiles afford lower intra-patient variability and an extended duration of action, providing full and stable 24?hour basal insulin coverage with once daily dosing, and comparable efficacy to insulin glargine with lower rates of hypoglycemia.

Conclusion: The improved pharmacodynamic/pharmacokinetic profiles of new long-acting insulin formulations provide greater glycemic control with once daily dosing. With the growing number of therapeutic choices available, physicians have more scope to individualize patient options for basal insulin therapy.     

Emerging therapies for the treatment of patients with advanced neuroendocrine tumors

Patients with neuroendocrine tumors may pursue a number of treatment options, but there is little consensus on a single, standard treatment approach. Somatostatin analogs are generally administered to patients with symptoms of hormonal secretion, and are often highly effective in this regard. However, the administration of somatostatin analogs is only rarely associated with tumor regression, and randomized trials demonstrating a survival benefit associated with their use have not been performed. Selected patients with hepatic metastases may undergo surgical debulking, embolization or other ablative therapies. The clinical benefit associated with administration of systemic agents such as IFN-α or cytotoxic chemotherapy has been limited. With the possible exception of streptozocin-based therapy in patients with pancreatic neuroendocrine tumors, the widespread use of standard cytotoxic regimens has been limited by their relatively modest antitumor activity, as well as concerns regarding their potential toxicity. The modest efficacy seen with these agents in patients with advanced neuroendocrine tumors has led to great interest in the development of novel treatment approaches. One such approach is the use of radiolabeled somatostatin analogs. Recently, agents targeting the VEGF pathway and mammalian target of rapamycin have also shown promise in patients with advanced neuroendocrine tumors. Ongoing randomized studies should help better define the role these agents will play in the future treatment of patients with this disease.     

不同的降压治疗方案对高血压脑出血病人神经功能、炎症反应及预后的影响

目的 探讨强化降压与常规降压治疗对高血压脑出血(HICH)病人神经功能、炎症反应及病人预后的影响.方法 选取2016年3月至2019年3月信阳市中心医院收治的HICH病人108例,采用随机数字表法分为强化组和常规组各54例,强化组采用早期强化降血压治疗(3 h内将病人收缩压降至140 mmHg以下,并以120～140 ...     

Understanding the Effects of Stimulant Medications on Cognition in Individuals with Attention-Deficit Hyperactivity Disorder: A Decade of Progress

The use of stimulant drugs for the treatment of children with attention-deficit hyperactivity disorder (ADHD) is one of the most widespread pharmacological interventions in child psychiatry and behavioral pediatrics. This treatment is well grounded on controlled studies showing efficacy of low oral doses of methylphenidate and amphetamine in reducing the behavioral symptoms of the disorder as reported by parents and teachers, both for the cognitive (inattention and impulsivity) and non-cognitive (hyperactivity) domains. Our main aim is to review the objectively measured cognitive effects that accompany the subjectively assessed clinical responses to stimulant medications. Recently, methods from the cognitive neurosciences have been used to provide information about brain processes that underlie the cognitive deficits of ADHD and the cognitive effects of stimulant medications. We will review some key findings from the recent literature, and then offer interpretations of the progress that has been made over the past decade in understanding the cognitive effects of stimulant medication on individuals with ADHD.     

The principle and the potential approach to ROS-dependent cytotoxicity by non-pharmaceutical therapies: optimal use of medical gases with antioxidant properties

Regulation of cellular redox balances is important for the homeostasis of human health. Thus, many important human diseases, such as inflammation, diabetes, glaucoma, cancers, ischemia and neurodegenerative diseases, have been investigated in the field of reactive oxygen species (ROS) and oxidative stress. To overcome the harmful effect of oxidative stress and ROS, one can directly eliminate them by medical gases such as carbon monoxide (CO), hydrogen sulphide (H(2)S), and molecular hydrogen (H(2)), or one can induce ROS-resistant proteins and antioxidant enzymes to antagonize oxidative stresses. This article reviews the molecular mechanisms how these medical gasses work as antioxidants, and how ROS resistant proteins are produced in the physiological context. Targeted therapeutic modalities to scavenge or prevent ROS might be applied in the prevention and treatment of ROS-related diseases in the near future.     

Pro-active provision of drug information as a technique to address overdosing in intensive-care patients with renal insufficiency

Purpose  To correct overdosing of drugs requiring adjustment based on renal function in intensive-care patients. Methods  In a prospective intervention study, we estimated individual glomerular filtration rate and assessed whether medication required dose adjustment based on renal function. Senior clinicians received a structured report containing recommendations as to whether and how to adjust dosage in the individual patient (intervention). Prevalence of overdosed drugs (primary outcome), extent of overdoses, and reasons for nonacceptance of recommendations (secondary outcomes) were assessed. Results  Of 138 screened intensive-care patients, 68 (49%) had renal impairment, and 110 (14%) of the 805 prescribed drugs required consideration of renal function. A potential overdose was found in 53/110 drugs (48%) and this rate decreased to 26/110 (24%, P < 0.001) after the intervention. The average extent of overdose was reduced from 54% before to 31% after the intervention (P < 0.001). The main reasons expressed by the physicians for nonacceptance of recommendations were a large therapeutic index or minor overdoses of the involved drugs. Conclusions  In intensive-care patients, overdosing of drugs requiring adjustment based on renal function is still very common. Drug information counselling significantly decreased the prevalence and extent of overdose.     

老年慢性肾功能衰竭患者幽门螺杆菌感染治疗前后血氨的变化

目的：观察研究老年慢性肾功能衰竭患者在接受幽门螺杆菌感染治疗前、后血氨的变化情况。方法：选择我院收治的老年慢性肾功能衰竭且幽门螺杆菌阳性患者84例作为观察组,并将幽门螺杆菌检出阴性的84例作为对照组。对两组患者的血氨检测值进行综合对比与分析。结果：观察组患者接受治疗前,血氨检测均值为（27.1±2.3）umol/L,明显高于对照组（P＜0.05）;观察组患者接受治疗后,血氨检测均值为（11.2±1.5）umol/L,明显低于接受治疗前（P＜0.05）,差异具有统计学意义。结论：老年慢性肾功能衰竭患者出现幽门螺杆菌感染症状后会导致机体血氨明显升高,对其进行幽门螺杆菌抗感染治疗有积极疗效,可降低血氨检测值,对延缓肾功能衰竭意义显著,值得临床关注并研究。     

江苏省晚期血吸虫病医疗救助情况调查

目的分析江苏省晚期血吸虫病医疗救助情况,为项目的可持续开展提供依据。方法调查对象根据受助情况分成受助组和对照组。采用《江苏省晚期血吸虫患者医疗救助项目评估问卷表》进行问卷调查。结果晚血患者年龄大,经济收入低,约1/3患者因经济困难存在患病未就医情况;87.2%的晚血患者认为晚血医疗救助政策是项好政策,但政策的知晓率在对照组中仅为51.5%,知晓的主要途径是通过卫生工作人员;医疗救助改善了患者的生命质量,且改善程度随治疗次数的增加而增加。结论持续的医疗救助有助于晚血患者生命质量的明显提高,但尚需提高政策的知晓率,加强医疗救助的针对性。