HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly-6C(high) inflammatory monocytes in murine sepsis survivors.

BACKGROUND: More than 500,000 hospitalized patients survive severe sepsis annually in the USA. Recent epidemiological evidence, however, demonstrated that these survivors have significant morbidity and mortality, with 3-year fatality rates higher than 70%. To investigate the mechanisms underlying persistent functional impairment in sepsis survivors, here we developed a model to study severe sepsis survivors following cecal ligation and puncture (CLP). METHODS: Sepsis was induced in mice by CLP and survivors were followed for twelve weeks. Spleen and blood were collected and analyzed at different time points post-sepsis. RESULTS: We observed that sepsis survivors developed significant splenomegaly. Analysis of the splenic cellular compartments revealed a major expansion of the inflammatory CD11b+ Ly-6CHigh pool. Serum high-mobility group box 1 (HMGB1) levels in the sepsis surviving mice were significantly elevated for 4-6 weeks after post-sepsis, and administration of an anti-HMGB1 monoclonal antibody significantly attenuated splenomegaly as well as splenocyte priming. Administration of recombinant HMGB1 to naive mice induced similar splenomegaly, leukocytosis and splenocyte priming as observed in sepsis survivors. Interestingly analysis of circulating HMGB1 from sepsis survivors by mass spectroscopy demonstrated a stepwise increase of reduced form of HMGB1 (with known chemo-attractant properties) during the first 3 weeks, followed by disulphide form (with known inflammatory properties) 4-8 weeks after CLP. DISCUSSION: Our results indicate that prolonged elevation of HMGB1 is a necessary and sufficient mediator of splenomegaly and splenocyte expansion, as well as splenocyte inflammatory priming in murine severe sepsis survivors.

Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment.

Clinically similar asthma patients may develop airway obstruction by different mechanisms. Asthma treatments that specifically interfere with the 5-lipoxygenase (ALOX5) pathway provide a method to identify those patients in whom the products of the ALOX5 pathway (that is, the leukotrienes) contribute to the expression of the asthma phenotype. Failure of an asthma patient to respond to treatment with ALOX5-pathway modifiers indicates that leukotrienes are not critical to the expression of the asthmatic phenotype in that patient. We previously defined a family of DNA sequence variants in the core promoter of the gene ALOX5 (on chromosome 10q11.2) associated with diminished promoter-reporter activity in tissue culture. Because expression of ALOX5 is in part transcriptionally regulated, we reasoned that patients with these sequence variants may have diminished gene transcription, and therefore decreased ALOX5 product production and a diminished clinical response to treatment with a drug targeting this pathway. Such an effect indicates an interaction between gene promoter sequence variants and drug-treatment responses, that is, a pharmacogenetic effect of a promoter sequence on treatment responses.

Declines in Pregnancies among U.S. Adolescents from 2007 to 2017: Behavioral Contributors to the Trend.

STUDY OBJECTIVES: Adolescent pregnancies and births in the United States have undergone dramatic declines in recent decades. We aimed to estimate the contribution of changes in 3 proximal behaviors to these declines among 14- to 18-year-olds for 2007-2017: 1) delays in age at first sexual intercourse, 2) declines in number of sexual partners, and 3) changes in contraceptive use, particularly uptake of long-acting reversible contraception (LARC). DESIGN: We adapted an existing iterative dynamic population model and parameterized it using 6 waves of the Centers for Disease Control and Prevention's Youth Risk Behavior Survey. We compared pregnancies from observed behavioral trends with counterfactual scenarios that assumed constant behaviors over the decade. We calculated outcomes by cause, year, and age. RESULTS: We found that changes in these behaviors could explain pregnancy reductions of 496,200, 78,500, and 40,700 over the decade, respectively, with total medical and societal cost savings of $9.71 billion, $1.54 billion, and $796 million. LARC adoption, particularly among 18-year-olds, could explain much of the improvement from contraception use. The 3 factors together did not fully explain observed birth declines; adding a 50% decline in sex acts per partner did. CONCLUSIONS: Delays in first sexual intercourse contributed the most to declining births over this decade, although all behaviors considered had major effects. Differences from earlier models could result from differences in years and ages covered. Evidence-based teen pregnancy prevention programs, including comprehensive sex education, youth-friendly reproductive health services, and parental and community support, can continue to address these drivers and reduce teen pregnancy.

Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression.

The HTR1A -1019C>G genotype was associated with major depression in the Utah population. Linkage analysis on Utah pedigrees with strong family histories of major depression including only cases with the HTR1A -1019G allele revealed a linkage peak on chromosome 10 (maximum HLOD=4.4). Sequencing of all known genes in the linkage region revealed disease-segregating single-nucleotide polymorphisms (SNPs) in LHPP. LHPP SNPs were also associated with major depression in both Utah and Ashkenazi populations. Consistent with the linkage evidence, LHPP associations depended on HTR1A genotype. Lhpp or a product of a collinear brain-specific transcript, therefore, may interact with Htr1a in the pathogenesis of major depression.

CCR5, RANTES and SDF-1 polymorphisms and mother-to-child HIV-1 transmission.

Summary Among 288 HIV-1-infected, breastfeeding women who received zidovudine prophylaxis and were followed with their infants in Nairobi, we found no associations between maternal genetic polymorphisms in CCR5 (59029G/A, 59353T/C, 59356T/C, 59402G/A), RANTES (-403G/A) and SDF-1 (3'801G/A) and mother-to-child HIV-1 transmission; plasma, cervical and breastmilk viral loads; or breastmilk chemokine concentrations.

HIV testing men in the antenatal setting: understanding male non-disclosure.

Prevention of infant HIV is a powerful incentive for maternal HIV diagnosis and an opportunity to increase male HIV testing and disclosure of HIV status within couples. We examined male HIV disclosure in couples who attended a Nairobi antenatal clinic (ANC), had individual HIV testing, and were counselled to disclose to their partner. At two-week follow-up, men and women independently reported HIV disclosure. Of 2104 women, 1993 requested partner attendance; 313 male partners came, of whom 183 chose individual HIV testing. Of 106 couples who followed up, 93% of both partners reported disclosure by women versus 71% by men (P < 0.0001); 27% of men reported disclosure while their female partner reported not knowing partner HIV status. In these couples, male ANC HIV testing did not result in shared knowledge of HIV status. Couple counselling models that incorporate disclosure may yield greater HIV prevention benefits than offering individual partner HIV testing services at ANC.

OPTN policy regarding prioritization of patients with hepatopulmonary syndrome: does it provide equitable organ allocation?

United Network for Organ Transplantation (UNOS) policy 3.6.4.5.1 provides exception points to patients diagnosed with hepatopulmonary syndrome (HPS) to compensate for their reported increased mortality risk. We compared pre- and posttransplant and overall outcomes in 255 patients receiving exception points under this policy (HPS policy patients) with 32 358 nonexception control patients listed in the model for end-stage liver disease (MELD) era to determine whether the intent of the policy is being met. Overall, 92.5% of HPS policy patients versus 45.5% of controls had been transplanted, 5.1% versus 31.2% remained on waiting list and 1.5% versus 14.1% had died while awaiting transplant (p < 0.0001 for each comparison). Relative risk (RR) of death for HPS policy patients compared to controls was 0.158 (confidence interval [CI]: 0.059-0.420, p = 0.0002) pretransplant, and 0.827 (CI: 0.587-1.170, p = 0.28) posttransplant. Overall (combined waitlist and posttransplant) RR of death was 0.514 (CI: 0.374-0.707, p = 0.00004) compared with controls. After adjustment for laboratory MELD, overall RR was 0.807 (CI: 0.587-1.110, p = 0.19), indicating that HPS policy patients' mortality risk would be similar to that of controls had they been listed with their laboratory MELD score. HPS policy patients have a significant pretransplant survival advantage over standard liver transplant candidates because of the exception points awarded, and have similar posttransplant survival. Better criteria for diagnosing and grading of HPS are required.

Association of CYP3A5 polymorphisms with hypertension and antihypertensive response to verapamil.

In the CYP3A5 gene, the A>G (*3) and G>A (*6) polymorphisms result in severely decreased expression of CYP3A5 enzyme relative to a normal functional allele (*1). We sought to determine if the CYP3A5 genetic polymorphisms were associated with level of blood pressure (BP), risk of hypertension (HTN), and the antihypertensive response to verapamil. A total of 676 normotensive and hypertensive participants (mean age 49+/-8.2 years) from the Hypertension Genes study and 722 patients (mean age 66+/-9 years) from the International Verapamil/Trandolapril Study Genetic Substudy (INVEST-GENES) were genotyped for CYP3A5 to test for associations with BP, HTN, and in the latter cohort, antihypertensive response to verapamil. CYP3A5 haplotypes were determined using PHASE 2, with any allele containing either (*3) or (*6) designated as non functional. In the HTN genes population, there were no significant differences based on the number of functional CYP3A5 alleles, in systolic blood pressure (SBP) or diastolic blood pressure (DBP) among the normotensive whites or blacks (all P> or =0.70) or in allele frequency between normotensives and hypertensives. In INVEST-GENES, when controlled for baseline BP, race, age, and gender, untreated BP in carriers versus non carriers of a CYP3A5 functional allele was 158.2+/-13.7 and 154.8+/-13.7 (P=0.061), respectively. CYP3A5 functional allele status was marginally associated with the SBP response to verapamil in blacks (P=0.075) and Hispanics (P=0.056), but not in whites (P=0.40), with the effect being largely driven by higher SBP in the carriers of two functional alleles. There was no association with DBP response and CYP3A5 allele status. CYP3A5 genotype does not contribute importantly to BP or risk of HTN, but may influence response to calcium channel blockers in populations in which carrier status of two functional alleles is common.

Periacetabular osteotomy in patients with Down's syndrome.

We treated eight dysplastic acetabula in six skeletally mature patients with Down's syndrome by a modified Bernese periacetabular osteotomy. The mean age at the time of surgery was 16.5 years (12.8 to 28.5). Mean length of follow-up was five years (2 to 10.4).Pre-operatively the mean (Tonnis) acetabular angle was 28 degrees, the centre-edge angle was -9 degrees, and the extrusion index was 60%; post-operatively they were 3 degrees, 37 degrees, and 17%, respectively. Two patients with post-operative (Tonnis) acetabular angles > 10 degrees developed subluxation post-operatively and required secondary varus derotation femoral osteotomies. Another patient developed a late labral tear which was treated arthroscopically. All eight hips remain clinically stable, and are either asymptomatic or symptomatically improved. These results suggest that the modified Bernese periacetabular osteotomy can be used successfully in the treatment of acetabular dysplasia in patients with Down's syndrome.

Clinical correlates of insomnia in patients with chronic illness.

BACKGROUND: Patients with chronic insomnia are more likely to develop affective disorders, cardiac morbidity, and other adverse health outcomes, yet many clinicians tend to trivialize the complaint of insomnia or to attribute it only to psychiatric causes. OBJECTIVES: To estimate the prevalence and longitudinal course of insomnia in patients with documented chronic medical illness and/or depression and to quantify the associations between specific chronic conditions and insomnia. METHODS: The presence of mild or severe insomnia was based on responses to a sleep questionnaire completed by 3445 patients with at least 1 of 5 physician-identified chronic conditions (hypertension, diabetes, congestive heart failure, myocardial infarction, or depression) at baseline; a subsample of 1814 patients completed follow-up questionnaires at 2 years. Using multivariate techniques, we evaluated the relationship between chronic conditions, patient-reported comorbidities, and insomnia (complaints of initiating and maintaining sleep), adjusting for sociodemographics and health habits. RESULTS: Sixteen percent of study patients had severe and 34% had mild insomnia at baseline. At 2-year follow-up, 59% (95% confidence interval, 55%-63%) of patients with mild insomnia and 83% (95% confidence interval, 78%-88%) of patients with severe insomnia at baseline still had sleep problems. Odds ratios corresponding to mild and severe insomnia for key risk factors were as follows: current depressive disorder, 2.6 and 8.2; subthreshold depression, 2.2 and 3.4; congestive heart failure, 1.6 and 2.5; obstructive airway disease, 1.6 and 1.5; back problems, 1.4 and 1.5; hip impairment, 2.2 and 2.7; and prostate problems, 1.6 and 1.4. The majority of insomnia-comorbidity associations observed at baseline persisted at 2-year follow-up. CONCLUSIONS: Patients with insomnia require follow-up, as the majority continue to be bothered by difficulty initiating and maintaining sleep. In addition to detecting affective disorders in patients with insomnia, clinicians should focus on medical conditions that disturb sleep, especially cardiopulmonary disease, painful musculoskeletal conditions, and prostate problems.

Clonal composition of pituitary adenomas in patients with Cushing's disease: determination by X-chromosome inactivation analysis.

The synthesis and secretion of anterior pituitary hormones are subjected to a variety of positive and negative feedback mechanisms. Aberrancies of these highly regulated phenomena may lead to hyperplasia involving multiple cells of the anterior lobe. Alternatively, a rare genetic mutation in a single cell may precede its clonal expansion. Which of these mechanisms is operative in the development of corticotroph adenomas is not known. To examine this question, we studied the clonal composition of ACTH-producing pituitary adenomas from female patients with Cushing's disease by using X-chromosome inactivation analysis. Nine of 27 patients examined were heterozygous at 1 of the 2 X-chromosome-linked polymorphic loci, hypoxanthine-phosphoribosyl-transferase and phosphoglycerate-kinase. The methylation patterns of the hypoxanthine-phosphoribosyl-transferase and phosphoglycerate-kinase genes, distinguishing between the active and inactive alleles, were analyzed in DNA extracted from the central part of the tumor and compared with those of autologous lymphocyte DNA. Six tumors (4 microadenomas and 2 macroadenomas) showed a single active allele of the X-chromosome-linked genes and were monoclonal in nature. The other 3 pituitary adenomas (1 microadenoma and 2 macroadenomas, 1 from a patient with Nelson's syndrome) revealed a polyclonal pattern of X-chromosome inactivation. Our data demonstrate that corticotroph adenomas of the pituitary may arise from a single cell or from more than one cell. Whether fundamentally different endocrine mechanisms underlie the two processes remains to be seen.

Extrapituitary parasellar microadenoma in Cushing's disease.

Negative sellar exploration (despite the results of endocrine evaluation indicating Cushing's disease), the high incidence of failure of total hypophysectomy, and remission of Cushing's syndrome after unsuccessful hypophysectomy and sellar irradiation suggest that the etiology of refractory Cushing's disease, in some patients, lies near the sella but not in the pituitary gland. We present 5 patients, out of 626 who received surgery for Cushing's disease, in whom an ACTH-secreting extrapituitary parasellar adenoma was identified: 2 after unsuccessful total hypophysectomy for the treatment of refractory Cushing's disease, 2 after unsuccessful hemihypophysectomy (the first, 2 yr before treatment at the NIH for Nelson's syndrome; and the second, with recurrent Cushing's disease 5 yr after negative transsphenoidal exploration), and 1 with a preoperative diagnosis of an intraclival microadenoma, which was cured by resection of the tumor. In all cases, an extrapituitary parasellar microadenoma was confirmed unequivocally as the cause of the disease, by negative pathology of the resected pituitary gland (patients 1, 2, 3, and 5), and/or the remission of the disease after selective resection of the extrasellar adenoma (patients 3, 4, and 5). Three of 5 patients had a partial empty sella. These patients support the thesis that ACTH-secreting tumors can arise exclusively from remnants of Rathke's pouch, rather than from the adenohypophysis (anterior lobe or pars tuberalis of the pituitary gland) and can be a cause of Cushing's disease. In the sixth presented case, an extrapituitary tumor was suspected at surgery after negative pituitary exploration, but serial sections of the hemihypophysectomy specimen revealed a microscopic focus of tumor at the margin of the resected gland. This case demonstrates the importance of negative pituitary histology to establish the presence of an extrapituitary parasellar tumor as an exclusive source of ACTH, and it supports the value of clinical outcome to establish the diagnosis with selective adenomectomy of an extrapituitary parasellar tumor. In patients with negative pituitary magnetic resonance imaging, especially in the presence of a partial empty sella, the diagnostic and surgical approach in Cushing's disease should consider the identification and resection of extrapituitary parasellar adenoma, which can avoid total hypophysectomy, as was possible in 3 of our 5 patients.

Nelson's syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene.

Nelson's syndrome is the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for Cushing's disease. Extremely high plasma ACTH levels and aggressive neoplastic growth might be explained by the lack of appropriate glucocorticoid negative feedback due to defective glucocorticoid signal transduction. To study the glucocorticoid receptor (GR) gene in Nelson's syndrome, DNA was extracted from pituitary adenomas and leukocytes of four patients with this condition and amplified by PCR for direct sequence analysis. In one of the tumors, a heterozygous mutation, consisting of an insertion of a thymine between complementary DNA nucleotides 1188 and 1189, was found in exon 2. This frame-shift mutation led to premature termination at amino acid residue 366 of the wild-type coding sequence, excluding the expression of a functioning receptor protein from the defective allele. The mutation was not detected in the sequence of the GR gene in the patient's leukocyte DNA, indicating a somatic origin. By lowering the receptor number in tumorous cells, this defect might have caused local resistance to negative glucocorticoid feedback similar to that caused by the presence of a null allele in a kindred with the generalized glucocorticoid resistance syndrome. P53 protein accumulation, previously reported in 60% of corticotropinomas, could not be detected in any of the four pituitary tumors examined by immunohistochemistry. We suggest that a somatic GR defect might have played a pathophysiological role in the tumorigenesis of the corticotropinoma bearing this mutation.

Thyrotropin-secreting pituitary carcinoma.

Pituitary tumors rarely metastasize outside the central nervous system. Of the more than 100 reported TSH-secreting adenomas, we now describe the first carcinoma. A 40-yr-old woman had transsphenoidal surgery for a large TSH-secreting pituitary adenoma in 1984. She had increased thyroid hormone levels with a TSH that varied from 16-31 microU/mL, and an unusually high alpha-subunit that ranged from 125-150 ng/mL. Because of residual tumor, she had a left craniotomy in 1985 followed by radiation. Despite these therapies, she had a residual tumor that remained stable until January 1989 when her tumor nearly doubled in size. She received radiation therapy and octreotide with marked diminution of the tumor and clinical improvement. In August 1989, she presented with leg weakness, and magnetic resonance imaging revealed a large sacral mass. A biopsy confirmed that the sacral mass was a metastasis from the pituitary tumor. Due to additional metastases in the lung, she received 5-fluorouracil, cytoxan, and adriamycin, with marked decrease in her lesions. Further substantiation of the metastatic pituitary tumor was made when the patient returned in December 1989 with a pleural effusion containing pituitary tumor cells. Of all the reported cases of TSH-secreting adenomas, this case had the highest alpha-subunit portending future metastases. Furthermore, the apparent response to octreotide and response to chemotherapy are encouraging and suggest that new therapies should be explored. Finally, since TSH-secreting adenomas tend to be more invasive than other pituitary tumors, this case underscores the need for early diagnosis and aggressive treatment of these tumors.

Neurosyphilis in acquired immunodeficiency syndrome.

In a retrospective study encompassing 42 months (January 1984 through July 1987), 12 patients were identified as having both neurosyphilis and acquired immunodeficiency syndrome. These patients constituted 44% of the entire group meeting rigorous diagnostic criteria for neurosyphilis and 1.5% of all patients hospitalized with acquired immunodeficiency syndrome. The typical patient with acquired immunodeficiency syndrome and neurosyphilis was young (mean age, 37 years) and male (83%). All had serological evidence of syphilis in both blood and cerebrospinal fluid. Syphilitic eye disease was surprisingly common in this group, occurring in 5 (42%). Four patients (33%) had been previously treated for syphilis. In 2, treatment for latent syphilis had been completed 3 and 5 months, respectively, before neurosyphilis was documented. Neurosyphilis is not uncommon in patients with acquired immunodeficiency syndrome in our population. In light of its diverse manifestations, syphilis should be considered in the differential diagnosis of any human immunodeficiency virus type 1-infected individual presenting with neurological, psychiatric, or ophthalmological disease.

Neurosyphilis. A comparative study of the effects of infection with human immunodeficiency virus.

BACKGROUND: The course of neurosyphilis has been reported to be altered by human immunodeficiency virus (HIV) infection. Prior reports of neurosyphilis occurring in association with HIV infection have been largely anecdotal and have failed to compare neurosyphilis in patients with HIV infection with an uninfected control group. This study was performed to determine if the clinical presentation encountered is different in the presence of HIV infection. DESIGN: A retrospective, hospital-based, case series study based on chart review encompassing a 64-month period. SETTING: The study was performed in a large, university-affiliated, public health trust hospital in south Florida. PATIENTS: Forty-six hospitalized patients with neurosyphilis were identified; 13 patients fulfilled Centers for Disease Control and Prevention (Atlanta, Ga) criteria for acquired immunodeficiency syndrome (AIDS), 11 were HIV seropositive only, and 22 were HIV uninfected. Neurosyphilis was determined by a reactive cerebrospinal fluid VDRL slide test. RESULTS: The HIV-infected patients (both AIDS and HIV-seropositive groups) were younger and more frequently had features of secondary syphilis, such as rash, fever, adenopathy, headache, or meningismus. Significant differences were observed in cerebrospinal fluid measurements when the HIV-infected group was compared with the HIV-uninfected group, including a higher mean white blood cell count in patients with AIDS and a higher mean protein level and a lower mean glucose level in the HIV-infected group. Syphilitic meningitis was more common in HIV-seropositive patients, although the HIV-uninfected patients presented with a greater variety of types of neurosyphilis. Ophthalmic syphilis was observed more frequently in the HIV-infected group. CONCLUSIONS: Significant differences exist between neurosyphilis occurring in the presence and absence of HIV infection.

Peripheral neuropathy in cerebrotendinous xanthomatosis.

We performed a sural nerve biopsy in a patient with cerebrotendinous xanthomatosis (CTX) because of electrophysiologic evidence of peripheral neuropathy. The sections showed a striking loss of myelinated axons, the distribution of which suggested a compressive and/or ischemic process. Biochemical analysis disclosed large amounts of cholestanol, a cholesterol derivative that characteristically accumulates in CTX. However, the biochemical abnormality was not associated with any obvious structural alterations in the myelin lamellae or with abnormal storage material in Schwann's cells.

Clinical and pathological features of an autosomal dominant, adult-onset leukodystrophy simulating chronic progressive multiple sclerosis.

OBJECTIVE: To study the clinical and pathological features of a kindred with an adult-onset autosomal dominant leukodystrophy. PATIENTS: Five symptomatic and nine asymptomatic at-risk members of the kindred. INTERVENTIONS: Subjects underwent detailed histories and general and neurologic examinations. Further evaluation included electroencephalography, evoked potentials, electromyography, autonomic testing, and analysis of serum, urine, and cerebrospinal fluid. One patient underwent sural nerve biopsy and analysis. Another, previously studied patient, underwent a limited autopsy. RESULTS: Cerebellar and pyramidal dysfunction began in the fourth and fifth decades of life; subtle autonomic symptoms were often present years earlier. Frontal lobe dysfunction and abnormalities of the central visual pathways were mild and of late onset. Sensorineural hearing loss was common. The peripheral nervous system was spared. Autopsy results of one patient revealed severe degeneration of the white matter at all levels of the neuraxis, but most prominent in the frontoparietal and cerebellar regions, with sparing of the subcortical U fibers. Histological and ultrastructural examinations failed to show evidence of a specific pathogenetic mechanism or etiology. CONCLUSION: This disorder seems to be a distinct type of hereditary leukodystrophy, but its exact nature remains unknown.

Progressive multifocal leukoencephalopathy complicating Wiskott-Aldrich syndrome. Report of a case and review of the literature of progressive multifocal leukoencephalopathy with other inherited immunodeficiency states.

OBJECTIVE: To describe the occurrence of progressive multifocal leukoencephalopathy (PML) in association with Wiskott-Aldrich syndrome, an X-linked recessive disorder with impairment of both cellular and humoral immunity. DESIGN: A detailed analysis of this patient's clinical illness, immunologic factors, neuroradiographic findings, and brain histopathologic conditions was undertaken. The medical literature on PML complicating congenital immunodeficient states was also reviewed. SETTING: A 1500-bed, university-affiliated, public health hospital. PATIENT: A 15-year-old boy with Wiskott-Aldrich syndrome. His neurologic illness was heralded by dysarthria and right-sided weakness and the diagnosis was established by brain biopsy specimen. Survival from the time of onset of PML was 10 months. CONCLUSION: Although PML typically occurs in the setting of severe acquired cellular immunodeficiency, often as a consequence of acquired immunodeficiency syndrome, organ transplantation, and leukemia and lymphoma, it may rarely accompany inherited immunodeficiency syndromes. The reported childhood cases of PML include three patients, aged 5, 11, and 18 years, with other inherited immunodeficiency syndromes. This patient represents the first time (to our knowledge) that PML has been reported to occur in association with Wiskott-Aldrich syndrome.

Brain growth and cognitive improvement in children with human immunodeficiency virus-induced encephalopathy after 6 months of continuous infusion zidovudine therapy.

The ventricular area at the level of the foramen of Monro was measured from axial x-ray computed tomography (CT) scans obtained prior to and 6 months after the initiation of continuous infusion of zidovudine (ZDV) in eight children with human immunodeficiency virus-induced encephalopathy. Evidence of moderate to severe central atrophy was present on initial CT scans (p less than 0.05). Ventricular area and ventricular brain area ratio (VBR) decreased after ZDV therapy in seven of eight children (mean decrease of 21.5 and 20%, respectively, p less than 0.05). The degree of decrease in VBR correlated with reductions in cerebrospinal fluid (CSF) protein concentration (r = 0.93, p less than 0.01), but not lymphocyte T4 or T8 counts. Intelligence quotients (IQs) improved in all seven children tested (mean improvement of 17.7%, p less than 0.01) and correlated significantly with reductions in CSF protein concentration (r = -0.85, p = 0.003). The magnitude of IQ changes was not significantly correlated with the magnitude of changes in ventricular area. We conclude that the cognitive improvement of HIV encephalopathy seen after 6 months of continuous infusion of ZDV is accompanied by reduction in brain atrophy and decreased CSF protein, suggesting an ameliorating effect of ZDV on the pathogenesis of AIDS encephalopathy in children.