Expression patterns of corticotropin-releasing factor, arginine vasopressin, histidine decarboxylase, melanin-concentrating hormone, and orexin genes in the human hypothalamus

The hypothalamus regulates numerous autonomic responses and behaviors. The neuroactive substances corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), histidine decarboxylase (HDC), melanin-concentrating hormone (MCH), and orexin/hypocretins (ORX) produced in the hypothalamus mediate a subset of these processes. Although the expression patterns of these genes have been well studied in rodents, less is known about them in humans. We combined classical histological techniques with in situ hybridization histochemistry to produce both 2D and 3D images and to visually align and quantify expression of the genes for these substances in nuclei of the human hypothalamus. The hypothalamus was arbitrarily divided into rostral, intermediate, and caudal regions. The rostral region, containing the paraventricular nucleus (PVN), was defined by discrete localization of CRF- and AVP-expressing neurons, whereas distinct relationships between HDC, MCH, and ORX mRNA-expressing neurons delineated specific levels within the intermediate and caudal regions. Quantitative mRNA signal intensity measurements revealed no significant differences in overall CRF or AVP expression at any rostrocaudal level of the PVN. HDC mRNA expression was highest at the level of the premammillary area, which included the dorsomedial and tuberomammillary nuclei as well as the dorsolateral hypothalamic area. In addition, the overall intensity of hybridization signal exhibited by both MCH and ORX mRNA-expressing neurons peaked in distinct intermediate and caudal hypothalamic regions. These results suggest that human hypothalamic neurons involved in the regulation of the HPA axis display distinct neurochemical patterns that may encompass multiple local nuclei.     

CE: Continuing Education ArticleMANAGEMENT OF ANAEMIA IN CHRONIC KIDNEY DISEASE

Anaemia is an almost universal issue that develops in the later stages of chronic kidney disease (CKD) primarily due to a lack of erythropoietin (EPO) and the depressed EPO response in bone marrow. This can have a profound effect on the patient's lifestyle and quality of life. Knowledge of both the psychosocial and clinical areas of CKD is imperative for healthcare professionals so that they can be at the forefront of improvements of CKD patient care.     

Dyslipidaemia and statin use in individuals aged 10 to <40 years in the T1D Exchange clinic registry

For individuals aged 10 to <40 years with type 1 diabetes and dyslipidaemia, US national guidelines recommend consideration of statin therapy based on age, low-density lipoprotein cholesterol (LDL-C) level and other cardiovascular risk factors. We evaluated dyslipidaemia prevalence, statin therapy use, and associations between not meeting target LDL-C [<100 mg/dL (<5.55 mmol/L)] and other cardiovascular disease (CVD) risk factors in individuals aged 10 to <40 years in the T1D Exchange clinic registry. In 7223 participants, statin use was 2% in 10 to <18 year olds, 4% in 18 to <25 year olds, and 21% in 25 to <40 year olds. Individuals not on statin therapy with LDL-C above target were more likely to have ≥1 additional CVD risk factor(s) than those with LDL-C in the target range for all age groups (all P < 0.01). While most individuals not on statin therapy had LDL-C in the target range, those who did not were more likely to have ≥1 additional CVD risk factor(s), and therefore longitudinal study of lipid levels and statin use is needed to see if treatment of dyslipidaemia to target LDL-C levels may lower the risk of future CVD in individuals aged 10 to <40 years with type 1 diabetes.     

Inequities in Health Outcomes in Children and Adults With Type 1 Diabetes: Data From the T1D Exchange Quality Improvement Collaborative

Health care inequities among racial and ethnic groups remain prevalent. For people with type 1 diabetes who require increased medical access and care, disparities are seen in access to care and health outcomes. This article reports on a study by the T1D Exchange Quality Improvement Collaborative evaluating differences in A1C, diabetic ketoacidosis (DKA), severe hypoglycemia, and technology use among racial and ethnic groups. In a diverse cohort of nearly 20,000 children and adults with type 1 diabetes, A1C was found to differ significantly among racial and ethnic groups. Non-Hispanic Blacks had higher rates of DKA and severe hypoglycemia and the lowest rate of technology use. These results underscore the crucial need to study and overcome the barriers that lead to inequities in the care and outcomes of people with type 1 diabetes.

Health inequities among racial and ethnic groups persist in both children and adults. Individuals with chronic conditions such as type 1 diabetes require increased medical access and care. Yet, there are disparities in access to care and health outcomes (1). The incidence of type 1 diabetes is increasing in the United States across all populations, and most significantly among Hispanic youths, but despite the higher incidence, health disparities continue to worsen among specific racial and ethnic groups (2,3).Mean A1C levels were found to be higher in Hispanics and non-Hispanic Blacks with type 1 diabetes compared with non-Hispanic Whites in the largest U.S. study to date, which included ∼11,000 youths and young adults in the T1D Exchange clinic network and registry (4). Non-Hispanic Blacks and Hispanics have been reported to perform fewer blood glucose checks per day than Non-Hispanic Whites (5,6). One study evaluating A1C trajectories over time in ∼16,000 youths from Australia, Europe, and the United States found that minority groups were more likely to have increasing A1C levels over time compared with Non-Hispanic Whites, specifically in the T1D Exchange and Diabetes-Patienten-Verlaufsdokumentation registries (7).Disparities also exist in rates of acute complications such as diabetic ketoacidosis (DKA) and severe hypoglycemia, although literature in this area is more limited. One study found that Non-Hispanic Blacks were 2.5 times more likely to have at least one DKA episode in the previous 12 months compared with Non-Hispanic Whites. They were also 2.5 times more likely than Non-Hispanic Whites to have at least one severe hypoglycemic event in the previous 12 months (4). Rates of mortality in diabetes are also twice as high among Non-Hispanic Blacks compared with other racial groups (8).One area of diabetes care that has improved diabetes management is the advancement of technology, including insulin pumps and continuous glucose monitoring (CGM) systems. However, use of these advanced diabetes technologies varies by population. Both the T1D Exchange and the SEARCH for Diabetes in Youth registries reported that Non-Hispanic White youths are more likely to use an insulin pump than their Black and Hispanic counterparts (4,9,10). The T1D Exchange registry found that Non-Hispanic White youths were 1.9 times more likely than Non-Hispanic Black youths and 3.6 times more likely than Hispanic youths to use an insulin pump. This finding is particularly important because it is known that insulin pump therapy can contribute to lower A1C levels (11), and Non-Hispanic Black and Hispanic youths are more likely to have higher A1C levels (4,7). Agarwal et al. (12) recently found that insulin pump use was one variable that helped account for the difference in A1C levels between Black and White young adults with type 1 diabetes. Studies of CGM use among racial and ethnic groups are very limited. One study showed that, among youths <13 years of age, Non-Hispanic Whites were more likely than Hispanics to use CGM, but this difference was not seen in older children or adults (13).Although there have been multiple studies evaluating A1C differences among racial and ethnic groups, there are limited population studies, and none have examined inequities in acute complication rates and technology use. This study uses a dataset with a large cohort of individuals with type 1 diabetes in a real-world setting to examine racial and ethnic differences in glycemic control, acute complications rates, and technology use.     

Internal fixation of fractures of both bones forearm: Comparison of locked compression and limited contact dynamic compression plate

Background:

The locking compression plate (LCP) with combination holes is a newer device in fracture fixation. We undertook a study comparing the LCP with limited contact dynamic compression plate (LC-DCP) in the treatment of diaphyseal fractures of both bones of the forearm.

Materials and Methods:

This is a prospective comparative study, 36 patients (18 in each group) with fractures of both the forearm bones (72 fractures) were treated with one of the two devices. The average age of the patients was 30.5 years (range 16–60 years) with mean followup of 2.1 years (range 1.5–2.8 years). The patients were assessed for fracture union and function and complications and by Disabilities of the Arm, Shoulder and Hand (DASH) score for patient related outcome at the latest followup.

Results:

There was no significant difference in two groups with respect to the range of movements or grip strength. One case had delayed union (LC-DCP group) and another had synostosis (LCP group). Plate removal was done in four cases within the study period with no refracture till the presentation of this report.

Conclusion:

LC plating is an effective treatment option for fractures of both bones of forearm. The present study could not prove its superiority over LC-DCP.     

Rapid-acting antidepressant strategies: mechanisms of action

Current antidepressants are ineffective in many depressed patients. Thus there is an urgent need to develop treatment strategies which have significantly faster response, can be sustained and have minimal side-effects. This paper reviews clinical data, potential biomarkers, mechanisms of action and future research directions for two proven strategies that produce marked improvement in severe depressive symptoms within 48 h, ketamine and sleep deprivation therapy (SDT). These treatments provide unequivocal evidence that the depressive process can be rapidly reversed in a subgroup of patients. Seventeen ketamine studies in over 150 patients showed a rapid response. Low-dose intravenous ketamine produced mild psychotomimetic effects but response has not been effectively sustained. SDT has been investigated in over 60 studies with a 40-60% response rate within 48 h. Although SDT is often used in Europe to initiate a rapid response, it is less utilized within the USA, in part, because it has a short duration when administered alone. We review data concerning chronotherapeutic strategies of bright-light therapy (BLT) and sleep-phase advance (SPA) which successfully sustain the antidepressant efficacy of SDT. Evidence is further discussed that a significant group of mood disorders have abnormal circadian rhythms which are known to be controlled by clock genes. It is hypothesized that chronotherapeutic manipulations can reset clock genes and thus, abnormalities in circadian rhythms. Further findings are reviewed that ketamine, in addition to its role as an NMDA antagonist, can also alter circadian rhythms. Thus, ketamine may share a critical mechanism with SDT.     

Electrophysiological studies on the specificity of the cholecystokinin antagonist proglumide

Recent evidence suggests that the glutaramic acid derivative proglumide (PROG) is a selective antagonist of cholecystokinin (CCK) in the rat CNS. The extent of this selectivity has now been characterized in more detail. Iontophoretic or intravenous (i.v.) administration of PROG was ineffective against the excitatory effect of iontophoretically applied neurotensin on midbrain dopamine (DA) cells, the excitatory effect of substance P and the inhibitory effect of Met-enkephalin on prefrontal cortical neurons, and the inhibitory effect of histamine on neurons of the sensorimotor cortex. In contrast, PROG blocked the excitatory effect of the C-terminal octapeptide of CCK in all 3 areas. Furthermore, iontophoretic PROG diminished, whereas CCK enhanced the inhibitory effect of similarly applied DA and GABA on DA cells. PROG pretreatment (1 mg/kg, i.v.) reduced the inhibitory potency and maximum effect of i.v. apomorphine (APO) on A₉ DA neurons, while the inhibitory potency of APO was enhanced by i.v. CCK. Pretreatment with PROG plus CCK resulted in APO effects which were no different from those after PROG alone. Chronic treatment with PROG (1 mg/kg, p.o., 21 days) resulted in a return to normal of DA cell APO sensitivity. Combined, these findings suggest that PROG may be a relatively selective CCK antagonist, that the functional effect of dendritically released DA may be influenced by endogenously released CCK, and that tolerance may develop to the effects of chronic CCK receptor blockade.     

IMMUNOELECTRON MICROSCOPIC LOCALIZATION OF GROWTH FACTORS AND OTHER MARKERS IN HUMAN LONG－TERM BONE MARROW CULTURES

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