Autism‐associated Shank3 mutations alter mGluR expression and mGluR‐dependent but not NMDA receptor‐dependent long‐term depression

SHANK3 is a postsynaptic structural protein localized at excitatory glutamatergic synapses in which deletions and mutations have been implicated in patients with autism spectrum disorders (ASD). The expression of Shank3 ASD mutations causes impairments in ionotropic glutamate receptor‐mediated synaptic responses in neurons, which is thought to underlie ASD‐related behaviors, thereby indicating glutamatergic synaptopathy as one of the major pathogenic mechanisms. However, little is known about the functional consequences of ASD‐associated mutations in Shank3 on another important set of glutamate receptors, group I metabotropic glutamate receptors (mGluRs). Here, we further assessed how Shank3 mutations identified in patients with ASD (one de novo InsG mutation and two inherited point mutations, R87C and R375C) disrupt group I mGluR (mGluR1 and mGluR5) expression and function. To identify potential isoform‐specific deficits induced by ASD‐associated Shank3 mutations on group I mGluRs, we surface immunolabeled mGluR1 and mGluR5 independently. We also induced mGluR‐dependent synaptic plasticity (R,S‐3,5‐dihydroxyphenylglycine [DHPG]‐induced long‐term depression [LTD]) as well as N‐methyl‐D‐aspartate receptor (NMDAR)‐dependent LTD. ASD‐associated mutations in Shank3 differentially interfered with the ability of cultured hippocampal neurons to express mGluR5 and mGluR1 at synapses. Intriguingly, all ASD Shank3 mutations impaired mGluR‐dependent LTD without altering NMDAR‐dependent LTD. Our data show that the specific perturbation in mGluR‐dependent synaptic plasticity occurs in neurons expressing ASD‐associated Shank3 mutations, which may underpin synaptic dysfunction and subsequent behavioral deficits in ASD.     

Polypoid stromal lesions of the intestines

Interpretation of intestinal mesenchymal lesions is simplified merely by knowing in which anatomic layer they are usually found. For example, Kaposi sarcoma is detected on mucosal biopsies, whereas inflammatory fibroid polyp is almost always in the submucosa. Gastrointestinal stromal tumours (GIST) are centred generally in the muscularis propria. Schwannomas are essentially always in the muscularis propria. Knowledge of the favoured layer is also most important in interpreting colon biopsies, as many mesenchymal polyps are encountered in the colon. Herein we discuss several mesenchymal lesions and point out some diagnostic pitfalls.     

Identification of 22 novel loci associated with urinary biomarkers of albumin,sodium, and potassium excretion

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Thymic teratoma masquerading as a thyroid lump

Teratomas are germ cell tumours commonly found in the sacrococcygeal region, ovary, testicle or, infrequently, the mediastinum. In very rare circumstances, these tumours are found in the neck. This case represents a thymic teratoma presenting as what appeared to be an intrathyroid lesion. This has not been described previously and demonstrates an unusual presentation of a neck lump necessitating two operations and a multidisciplinary approach for management. We would also like to highlight that while patients undergo imaging to guide surgery, the surgeon must always be prepared for the unexpected and recognise situations where the operation should be converted to an exploratory procedure instead of full resection. Often, combined surgical care is the best option for difficult congenital cases.     

Characteristics and survival for HIV-associated multicentric Castleman disease in Malawi

Introduction

Clinical reports of multicentric Castleman disease (MCD) from sub-Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma-associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region.

Methods

We describe HIV-positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi''s 16 million people. We included adult patients≥18 years of age with HIV-associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015.

Results and discussion

MCD patients had a median age of 42.4 years (range 37.2–51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status ≥3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6–9.3) than KS (11.0 g/dL, range 9.1–12.0, p=0.011) or NHL (11.2 g/dL, range 4.5–15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7–3.2) than KS (3.7 g/dL, range 3.2–3.9, p=0.013) or NHL (3.4 g/dL, range 1.8–4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/µL (range 108–1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2–105.3) than KS (14.2 months, range 6.8–21.9, p=0.039) or NHL (13.8 months, range 0.2–98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL.

Conclusions

HIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high mortality. Improvements in awareness, diagnostic facilities, treatment and supportive care are needed to address this likely under-recognized public health problem in SSA.