Persistent infection with neurotropic herpes viruses and cognitive impairment.

BACKGROUND: Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens. RESULTS: PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (ß = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status. CONCLUSIONS: Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Linkage analysis of schizophrenia in African-American families.

While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SIBPAL) and (2) treating only affected individuals as informative (using the program MERLIN). We also explore three definitions of affected status: narrowly defined schizophrenia; one broadened to include schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26 cM; SIBPAL p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48 cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73 cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27 cM; p from 0.0022 to 0.0000003); MERLIN results support the significance of the SIBPAL results (p=0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia.

The oxyphil cell in abnormal parathyroid glands. A study of 114 cases.

The parathyroid oxyphil cell is apparently capable of parathyroid hormone secretion. To investigate the significance of oxyphil cells in abnormal human parathyroid glands, we compared histologic and clinical features in a retrospective study of 114 cases of hyperparathyroidism, Parathyroid glands were classified by the presence or absence of significant numbers of oxyphil cells. Significant numbers of oxyphil cells were found in 91% of all cases of secondary hyperparathyroidism, 69% of all cases of single adenoma, and 55% of all cases of primary multiple-gland hyperparathyroidism. Oxyphil cells are more common in women. Among cases of primary multiple-gland hyperparathyroidism, oxyphil cells were associated with greater mean serum calcium levels (P = .003). The oxyphil cell of the parathyroid gland is associated with hyperparathyroidism, and may secrete more hormone than the chief cell.

Sudden infant death with periventricular leukomalacia.

Periventricular leukomalacia (PVL) is a form of cerebral infarction occurring in neonates, particularly in low-weight and premature infants. PVL is well-known to neonatologists, but generally considered nonfatal. Many infants with PVL die in the hospital with multiple medical problems. Those infants with PVL who survive because of intensive care will have serious motor and sensory deficits, but these problems are rarely recognized before one year of age. When infants with PVL die at home, death seems sudden and unexpected. However, it is important to distinguish death caused by PVL from the Sudden Infant Death Syndrome because the implications for the family are quite different. This case report emphasizes that PVL may be fatal.

Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence.

Emerging preclinical and clinical evidence suggests that pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid with pleiotropic actions in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further, pregnenolone administration results in elevations in downstream neurosteroids such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABA(A) receptor responses. In addition, pregnenolone administration elevates pregnenolone sulfate, a neurosteroid that positively modulates NMDA receptors. There are thus multiple mechanistic possibilities for pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone). Additional evidence consistent with a therapeutic role for pregnenolone in schizophrenia includes neurosteroid changes following administration of certain antipsychotics in rodent models. For example, clozapine elevates pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior antipsychotic efficacy [Marx et al. (2006a) Pharmacol Biochem Behav 84:598-608]. Further, pregnenolone levels appear to be altered in postmortem brain tissue from patients with schizophrenia compared to control subjects [Marx et al. (2006c) Neuropsychopharmacology 31:1249-1263], suggesting that neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing pregnenolone as a therapeutic agent in schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in pregnenolone and allopregnanolone post-treatment with this intervention were correlated with cognitive improvements [Marx et al. (2009) Neuropsychopharmacology 34:1885-1903]. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive pregnenolone, in addition to enduring effects in a small subset of patients receiving pregnenolone longer-term [Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA]. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive pregnenolone, in addition to increased attention and working memory performance [Ritsner et al. (2010) J Clin Psychiatry 71:1351-1362]. Future efforts in larger cohorts will be required to investigate pregnenolone as a possible therapeutic candidate in schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

The distribution of neurons expressing calcium-permeable AMPA receptors in the superficial laminae of the spinal cord dorsal horn.

The superficial dorsal horn is a major site of termination of nociceptive primary afferents. Fast excitatory synaptic transmission in this region is mediated mainly by release of glutamate onto postsynaptic AMPA and NMDA receptors. NMDA receptors are known to be Ca2+-permeable and to provide synaptically localized Ca2+ signals that mediate short-term and long-term changes in synaptic strength. Less well known is a subpopulation of AMPA receptors that is Ca2+-permeable and has been shown to be synaptically localized on dorsal horn neurons in culture (Gu et al., 1996) and expressed by dorsal horn neurons in situ (Nagy et al., 1994; Engelman et al., 1997). We used kainate-induced cobalt uptake as a functional marker of neurons expressing Ca2+-permeable AMPA receptors and combined this with markers of nociceptive primary afferents in the postnatal rat dorsal horn. We have shown that cobalt-positive neurons are located in lamina I and outer lamina II, a region strongly innervated by nociceptors. These cobalt-positive neurons colocalize with afferents labeled by LD2, and with the most dorsal region of capsaicin-sensitive and IB4- and LA4-positive afferents. In contrast, inner lamina II has a sparser distribution of cobalt-positive neurons. Some lamina I neurons expressing the NK1 receptor, the receptor for substance P, are also cobalt positive. These neurons are likely to be projection neurons in the nociceptive pathway. On the basis of all of these observations, we propose that Ca2+-permeable AMPA receptors are localized to mediate transmission of nociceptive information.

Hemoperfusion in a child who ingested diquat and died from pontine infarction and hemorrhage.

A 2 1/2 year old boy accidentally ingested the herbicide diquat. Progressive neurologic dysfunction preceded his death 143 hours after poisoning. Brain stem infarction and purpura were noted at post mortem and closely resembled the brain stem pathology in 3 of 7 adults who died after diquat ingestion. Renal, gastrointestinal and pulmonary involvement in this child also resembled that seen in adults after ingestion of diquat. Hemoperfusion was performed six times in an effort to lower the body diquat burden. Cellulose-coated, activated charcoal was first employed 40 hours postingestion and removed diquat from serum with clearances of 104 and 39 ml/minute at the initiation of hemoperfusion and 6 hours later, respectively. Serum diquat concentrations decreased rapidly during charcoal hemoperfusion. However, marked rebound in serum diquat concentrations were noted between charcoal treatments, indicating extensive sequestration of diquat by tissues. Thrombocytopenia and hypocalcemia, the major complications of charcoal hemoperfusion, were easily treated. Unlike charcoal, Amberlite XAD-4 resin hemoperfusion did not remove diquat from serum. Charcoal hemoperfusion may temporarily reduce serum diquat concentrations. Whether the early institution and daily performance of charcoal hemoperfusion will minimize diquat-induced damage to brain and other organs is not clear from this case and will only be determined in future studies.