Clinical implications of residual growth hormone (GH) response to provocative testing in adults with severe GH deficiency

CONTEXT: The diagnosis of GH deficiency (GHD) in adults is based on provocative tests of GH release, all influenced by clinical factors. It is unknown whether the amount of residual GH reserve under the cutoff value has any physiological implication. OBJECTIVES: We used a large pharmacoepidemiological database of adult GHD (KIMS) and tested the impact of confounding factors on GH release of no greater than 3 microg/liter after an insulin tolerance test (ITT) and evaluated its potential physiological role. DESIGN, SETTINGS, AND PATIENTS: A total of 1098 patients fulfilled the criteria of having a GH peak of no greater than 3 microg/liter during ITT as well as documented IGF-I levels. OUTCOMES: The impact of underlying hypothalamic-pituitary disease, age, gender, body weight, as well as treatment modalities such as irradiation on peak GH level to ITT was evaluated, and the correlations between GH peak and targets of GH action were analyzed. RESULTS: The GH response to ITT was regulated by gender, age, and the number of additional pituitary deficiencies. In a multivariate evaluation, the extent of hypothalamic-pituitary dysfunction was the most important single predictor of GH peak in ITT. GH peaks in ITT were positively related to IGF-I levels and high-density lipoprotein-cholesterol, as well as inversely to triglycerides. CONCLUSIONS: Even in adult severe GHD, GH release appears to be regulated by factors defined to play an important role in normal GH secretion. The impact of very low GH release on IGF-I and lipid parameters indicates a persistent physiological role of low GH concentrations in severely affected patients with GHD.     

Excision of misincorporated ribonucleotides in DNA by RNase H (type 2) and FEN-1 in cell-free extracts

Misincorporated ribonucleotides in DNA will cause DNA backbone distortion and may be targeted by DNA repair enzymes. Using double-stranded oligonucleotide probes containing a single ribose, we demonstrate a robust activity in human, yeast, and Escherichia coli cell-free extracts that nicks 5' of the ribose. The human and yeast extracts also make a subsequent cut 3' of the ribonucleotide releasing a ribonucleotide monophosphate. The resulting 1-nt gap is an ideal substrate for polymerase and ligase to complete a proposed repair sequence that effectively replaces the ribose with deoxyribose. Screening of yeast deletion mutant cells reveals that the initial nick is made by RNase H(35), a RNase H type 2 enzyme, and the second cut is made by Rad27p, the yeast homologue of human FEN-1 protein. RNase H type 2 enzymes are present in all kingdoms of life and are evolutionarily well conserved. We knocked out the corresponding rnhb gene in E. coli and show that extracts from this strain lack the nicking activity. Conversely, a highly purified archaeal RNase HII type 2 protein has a pronounced activity. To study substrate specificity, extracts were made from a yeast double mutant lacking the other main RNase H enzymes [RNase H1 and RNase H(70)], while maintaining RNase H(35). It was found that a single ribose is preferred as substrate over a stretch of riboses, further strengthening a proposed role of this enzyme in the repair of misincorporated ribonucleotides rather than (or in addition to) processing RNADNA hybrid molecules.     

Takotsubo triggered by acute myocardial infarction：a common but overlooked syndrome？

Takotsubo cardiomyopathy （TCM） is an acute cardiac syndrome characterized by extensive, but potentially reversible, left ventricular dysfunction in the absence of an explanatory coronary obstruction. Thus, TCM is distinct from coronary artery disease （CAD） and acute myocardial infarction （AMI）. However, substantial evidence for co-existing CAD in some TCM patients exist. Herein, we take this associa-tion one step further and present a case in which the patient simultaneously suffered from AMI and TCM, and in which we believe that a primary coronary event triggered TCM. An 88-year-old female presented with chest pain. Echocardiography revealed apical akinesia with hypercontractile bases. An occluded diagonal branch with suspected acute plaque rupture was identified on the angiogram, but could not explain the extent of akinesia. Cardiac function recovered completely. Thus, this patient adhered to current diagnostic criteria for TCM. TCM is a well-known complication for other conditions associated with somatic stress. It is therefore intuitive to assume that AMI, which also associates with somatic stress and elevated catecholamine, can cause TCM. Our case illustrates that TCM and AMI may occur simulta-neously. Although causality cannot be conclusively inferred from this association, the somatic stress associated with AMI may have caused TCM in this patient.     

Caries prevalence of 35-year-old Oslo citizens in 1973 and 1984

DMF teeth and surfaces were recorded in a random sample of 35-yr-old Oslo citizens (born 1949). The index values were related to selected independent variables: sex, years at school, oral hygiene status (OHI-S), periodontal conditions (PI), use of interdental cleaning devices and dental visiting habits. Data from the present investigation were analysed together with data from a similar study on 35-yr-olds in 1973 in order to detect possible changes over time. The mean DMFS-score in the present investigation was 85, indicating a high caries experience, mainly due to a high F-component. A statistically significant increase in the number of decayed surfaces was demonstrated concomitant with an increase in PI- and OHI-S scores. There were more carious surfaces among irregular dental visitors than among the regular visitors. No statistically significant differences in DMF-scores from 1973 to 1984 were detected, but there was a statistically significant reduction in the prevalence of untreated caries during this period. Furthermore, an increase in the number of filled surfaces from 1973 to 1984 and a reduction in the number of missing surfaces were registered. This may indicate a tendency towards restoring instead of extracting carious teeth during the last decade.     

Immunoglobulin A deficiency and oral health status: a case–control study

Introduction: Immunoglobulin A (IgA) is important for mucosal health. Selective IgA deficiency (IgAD) is the most common primary immunodeficiency but its effect on oral health is unclear. The aim of this study was to investigate dental, periodontal and oral mucosal health in IgAD individuals.
Material and methods: In total, 32 adult IgAD subjects were compared with 63 randomly selected individuals. Participants answered questionnaires regarding general and oral health and underwent oral examination, including examination using the periodontal screening and recording (PSR) system and dental examination using the DMF system.
Results: The IgAD individuals had significantly more often undergone tonsillectomy (44% versus 24%, p= 0.046 ) and adenoidectomy (31% versus 8%, p= 0.003 ) compared with the controls. Furthermore, the IgAD subjects reported having pharyngitis, stomatitis and herpes labialis significantly more often. There was no significant difference in periodontal health ( mean PSR index ; 1.87 versus 1.77) or dental health ( mean DMFS ; 51.3 versus 53.7 ) between the two cohorts. A positive correlation between Helicobacter pylori infection and severity of periodontitis was found ( p= 0.036).
Conclusion: IgAD predisposes to oral mucosal infections but does not influence periodontal or dental health. This is the first controlled study to include detailed clinical history and investigations, together with full oral and dental examination, in adults with IgAD.     

Proteasome function is required for platelet production

The proteasome inhibiter bortezomib has been successfully used to treat patients with relapsed multiple myeloma; however, many of these patients become thrombocytopenic, and it is not clear how the proteasome influences platelet production. Here we determined that pharmacologic inhibition of proteasome activity blocks proplatelet formation in human and mouse megakaryocytes. We also found that megakaryocytes isolated from mice deficient for PSMC1, an essential subunit of the 26S proteasome, fail to produce proplatelets. Consistent with decreased proplatelet formation, mice lacking PSMC1 in platelets (Psmc1^fl/fl Pf4-Cre mice) exhibited severe thrombocytopenia and died shortly after birth. The failure to produce proplatelets in proteasome-inhibited megakaryocytes was due to upregulation and hyperactivation of the small GTPase, RhoA, rather than NF-κB, as has been previously suggested. Inhibition of RhoA or its downstream target, Rho-associated protein kinase (ROCK), restored megakaryocyte proplatelet formation in the setting of proteasome inhibition in vitro. Similarly, fasudil, a ROCK inhibitor used clinically to treat cerebral vasospasm, restored platelet counts in adult mice that were made thrombocytopenic by tamoxifen-induced suppression of proteasome activity in megakaryocytes and platelets (Psmc1^fl/fl Pdgf-Cre-ER mice). These results indicate that proteasome function is critical for thrombopoiesis, and suggest inhibition of RhoA signaling as a potential strategy to treat thrombocytopenia in bortezomib-treated multiple myeloma patients.     

Rare Case of Takayasu Arteritis with Concurrent Aneurysmal Dilation and Stenosis

Takayasu arteritis is a rare, chronic large vessel vasculitis that primarily affects women aged 10 to 40 years of Asian descent. The inflammatory processes of the disease can result in stenosis and/or occlusion of the aorta and its branches, causing a wide range of symptoms. Rarely, damage of the elastic lamina or muscular media can cause aneurysmal dilation of the affected vessel. Diagnosis is based on the clinical presentation, laboratory proof of inflammation, and imaging finding of wall thickening in the acute phase and later arterial stenosis or occlusion. Management includes disease control with immunosuppression and some patients might require revascularization. Here, we present a rare case of Takayasu arteritis with both right common carotid artery aneurysmal dilation and stenosis at a conforming site. Although aneurysmal dilation has been sparsely reported in the Takayasu arteritis literature, our case may represent the distinct finding of concomitant dilation and stenosis in this disease.     

Genetics and experimental models of crystal-induced arthritis. Lessons learned from mice and men: is it crystal clear?

PURPOSE OF REVIEW: We examine the major genes in mice and humans involved in the pathogenesis of monosodium urate, calcium pyrophosphate dihydrate and hydroxyapatite crystal-induced arthritis. RECENT FINDINGS: Several genetic causes of renal disease associated with hyperuricemia and gout provide insight into genes involved in renal urate handling. Mutations or polymorphisms in exons 4 and 5 and intron 4 of urate transporter 1 may be independent genetic markers of hyperuricemia and gout. Genetic analysis supports the role of ANKH mutations in calcium pyrophosphate dihydrate-induced arthritis. ANKH gain-of-function mutations were confirmed by functional studies; however, the crystals formed in ATD5 cells were basic calcium phosphate, not calcium pyrophosphate dihydrate, underlying the significance of chondrocyte differentiation state and the factors regulating normal and pathological mineralization. Animal models have implicated a general model of crystal-induced inflammation involving innate immunity through the NALP3 (Natch domain, leucine-rich repeat, and PYD-containing protein 3) inflammasome signaling through the interleukin-1 receptor and its signaling protein myeloid differentiation primary response protein 88. SUMMARY: Genetic analysis has elucidated genes responsible for crystal formation and animal models have unveiled mechanisms in the development of crystal-induced arthritis. Future studies will hasten understanding of the pathology of crystal-induced arthritis and provide new therapies.     

The archaic distinction between functioning and nonfunctioning neuroendocrine neoplasms is no longer clinically relevant

Background  

Neuroendocrine neoplasms (NENs) are increasing in incidence and prevalence. This reflects greater clinical awareness, effective imaging, and increasing pathological diagnostic recognition. Although the identification and treatment of clinical neuroendocrine syndromes are established, there is confusion when a NEN has no discernible clinical symptoms.